813 results on '"CHORIOCARCINOMA"'
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2. [URINARY EXCRETION OF CHORIONIC GONADOTROPINS IN NORMAL AND PATHOLOGICAL PREGNANCY. QUANTITATIVE DETERMINATION BY AN IMMUNOLOGICAL METHOD].
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LEBECH PE
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- Female, Humans, Pregnancy, Abortion, Threatened, Abscess, Antigen-Antibody Reactions, Appendix, Chemical Phenomena, Chemistry, Choriocarcinoma, Chorionic Gonadotropin, Hydatidiform Mole, Pregnancy Complications, Pregnancy, Ectopic, Urine, Uterine Neoplasms
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- 1964
Catalog
3. Total human chorionic gonadotropin is a more suitable diagnostic marker of gestational trophoblastic diseases than the free β-subunit of human chorionic gonadotropin
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Hirokazu Usui, Atsuko Mikiya, Eri Katayama, Natsuko Nakamura, Asuka Sato, Hideo Matsui, Makio Shozu, and Kaori Koga
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Human chorionic gonadotropin ,Free β-subunit ,Gestational trophoblastic disease ,Choriocarcinoma ,Hydatidiform mole ,Medicine (General) ,R5-920 ,Chemistry ,QD1-999 - Abstract
Objectives: Human chorionic gonadotropin (hCG) levels are essential for the management of trophoblastic diseases. This study aimed to compare the sensitivities and relationships of two hCG measurement methods (total hCG and the free β-subunit of hCG) in managing gestational trophoblastic disease (GTD). Design and Methods: We analyzed data from patients treated for GTD at Chiba University Hospital between 2008 and 2019. We focused on cases where both total hCG (mIU/mL) and the free β-subunit of hCG (ng/mL) were measured on the same day. Results: Out of 80 patients (mean age 38.9 ± 11.7 years) and 158 measurements, 26 had values below the sensitivity threshold for both tests. Fifty-nine measurements were positive for total hCG but below the sensitivity threshold for the free β-subunit of hCG, whereas only two showed the opposite. Seventy-one measurements were positive for both total hCG and the free β-subunit of hCG. There was a significant correlation between total hCG and the free β-subunit of hCG with both positive values, (r = 0.94, p more...
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- 2023
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4. Ropivacaine Retards the Viability, Migration, and Invasion of Choriocarcinoma Cells by Regulating the Long Noncoding RNA OGFRP1/MicroRNA-4731-5p/HIF3A Axis
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Yaojun Lu, Juan Ding, Le Zhang, and Chen Yang
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Bioengineering ,medicine.disease_cause ,Applied Microbiology and Biotechnology ,Biochemistry ,Cell Movement ,Pregnancy ,microRNA ,Trophoblastic neoplasm ,medicine ,Humans ,Ropivacaine ,MTT assay ,Choriocarcinoma ,Molecular Biology ,reproductive and urinary physiology ,Cell Proliferation ,Chemistry ,medicine.disease ,female genital diseases and pregnancy complications ,Long non-coding RNA ,Repressor Proteins ,HIF3A ,MicroRNAs ,embryonic structures ,Cancer research ,Female ,RNA, Long Noncoding ,Apoptosis Regulatory Proteins ,Carcinogenesis ,Biotechnology ,medicine.drug - Abstract
Choriocarcinoma is an aggressive gestational trophoblastic neoplasm. This study attempted to explore the biological functions and underlying mechanisms by which ropivacaine restrains the progression of choriocarcinoma. The expression of long noncoding RNA OGFRP1, microRNA-4731-5p (miR-4731-5p), and HIF3A in choriocarcinoma cells was assessed by qRT-PCR. Choriocarcinoma cells treated with ropivacaine at the concentration of 100, 500, and 1000 μM were cultured for 24, 48, and 72 h, respectively. Choriocarcinoma cell viability was evaluated by MTT assay. Transwell assay was conducted to examine choriocarcinoma cell migration and invasion. Additionally, the target relationship between OGFRP1 and miR-4731-5p or between miR-4731-5p and HIF3A was predicted by bioinformatics analysis and confirmed by dual-luciferase reporter assays. OGFRP1 and HIF3A expression were enhanced in choriocarcinoma cells, while miR-4731-5p expression was inhibited. Treatment with ropivacaine impeded choriocarcinoma cell viability, migration, and invasion. Choriocarcinoma cells treated with 1000 μM ropivacaine for 48 h were selected for subsequent experiments. OGFRP1 elevation or miR-4731-5p deficiency mitigated the reduction effect of ropivacaine on tumorigenesis of choriocarcinoma cells. Besides, miR-4731-5p was predicted as the potential OGFRP1 target by StarBase and LncBase, and HIF3A was predicted as the potential miR-4731-5p target by StarBase and TargetScan. Dual-luciferase reporter assays determined that miR-4731-5p was a target of OGFRP1 and HIF3A was a target of miR-4731-5p. Feedback experiments declared that miR-4731-5p elevation or HIF3A suppression reversed the promoting effect of OGFRP1 overexpression on the malignant behaviors of ropivacaine-treated choriocarcinoma cells. Ropivacaine constrained choriocarcinoma cell viability, migration, and invasion through modulating the OGFRP1/miR-4731-5p/HIF3A axis. Our study may provide a novel strategy for choriocarcinoma prevention and treatment. more...
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- 2021
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5. Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial
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Hongyan Cheng, Yujia Kong, Xirun Wan, Yang Xiang, Xiaoyu Wang, Jun Zhao, Junjun Yang, Wei Cang, Liju Zong, and Yu Gu
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Adult ,China ,medicine.medical_specialty ,Pyridines ,medicine.medical_treatment ,Salvage therapy ,Angiogenesis Inhibitors ,Neutropenia ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,chemistry.chemical_compound ,Leukocytopenia ,Pregnancy ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Apatinib ,Gestational Trophoblastic Disease ,Adverse effect ,Immune Checkpoint Inhibitors ,Aged ,Chemotherapy ,business.industry ,Choriocarcinoma ,Middle Aged ,medicine.disease ,Treatment Outcome ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Female ,business - Abstract
Summary Background Treatment options for patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia are scarce. The synergistic antitumour effect of immunotherapy and antiangiogenic drugs has been shown in many solid tumours. This phase 2 trial evaluated the activity and safety of camrelizumab (PD-1 inhibitor) plus apatinib (VEGF receptor inhibitor) in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. Methods This was a single-arm, open-label, phase 2 trial, done at a single tertiary health-care centre in Beijing, China. Women (18–70 years) with high-risk (International Federation of Gynecology and Obstetrics score ≥7) chemorefractory or relapsed gestational trophoblastic neoplasia who had received at least two lines of previously unsuccessful multidrug chemotherapy regimens and had an Eastern Cooperative Oncology Group performance status of 0–2 were eligible for inclusion. Patients received 4-week cycles of intravenous camrelizumab 200 mg every 2 weeks plus oral apatinib 250 mg once per day until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed according to serum human chorionic gonadotrophin concentration. Activity and safety were analysed in all patients who received at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov , NCT04047017 . Findings Between Aug 7, 2019, and March 18, 2020, 20 patients enrolled; 19 (95%) were diagnosed with choriocarcinoma and one (5%) had placental site trophoblastic tumour. The median follow-up duration was 18·5 months (IQR 14·6–20·9). The objective response rate was 55% (95% CI 32–77); ten (50%; 95% CI 27–73) patients had complete response. The most common grade 3 treatment-related adverse events were hypertension (five [25%] patients), rash (four [20%] patients), neutropenia (two [10%]), leukocytopenia (two [10%]), and aspartate aminotransferase increase (two [10%]). One patient had a treatment-related serious adverse event (aspartate aminotransferase 19-times higher than the upper limit of normal). No grade 4 or 5 treatment-related adverse events were reported. Interpretation Camrelizumab plus apatinib showed promising antitumour activity and acceptable toxicity and could be a salvage therapy option for the treatment of high-risk chemorefractory or relapsed gestational trophoblastic neoplasia. Immune checkpoint inhibitors combined with chemotherapy for heavily-treated patients and upfront use of camrelizumab plus apatinib for patients with high-risk gestational trophoblastic neoplasia are under investigation in phase 2 trials. Funding National Natural Science Foundation of China, Jiangsu Hengrui Pharmaceuticals. more...
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- 2021
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6. Sensitive Tumor Cell Line for Annonaceous Acetogenins and High Therapeutic Efficacy at a Low Dose for Choriocarcinoma Therapy
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Likang Lu, Meihua Han, Yifei Guo, Haowen Li, Jingxin Fu, Hui Ao, and Xiangtao Wang
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Acetogenins ,Paclitaxel ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Bioengineering ,Pharmacology ,HeLa ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Animals ,Humans ,General Materials Science ,Choriocarcinoma ,Cytotoxicity ,IC50 ,biology ,Chemistry ,Lethal dose ,biology.organism_classification ,Acute toxicity ,Toxicity ,Nanoparticles ,HeLa Cells - Abstract
Annonaceous acetogenins (ACGs) have attracted much attention because of excellent antitumor activity. However, the lack of selectivity and the accompanying serious toxicity have eventually prevented ACGs from entering clinical application. To decrease the side effects of ACGs, the cytotoxicity of ACGs on 10 types of tumor cell lines was investigated by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) test to identify one that was very sensitive to ACGs. Meanwhile, ACGs nanoparticles (ACGs-NPs) were prepared using poloxamer 188 (P188) as an excipient so as to solve the problem of poor solubility and the in vivo delivery of ACGs. ACG-NPs were 163.9±2.5 nm in diameter, negatively charged, and spherical with a high drug loading content (DLC) of 44.9±1.2%. MTS assays demonstrated that ACGs had strong cytotoxicity against JEG-3, HeLa, SiHa, MCF-7, A375, A2058, A875, U-118MG, LN- 229, and A431 cells, among which JEG-3 cell line was extremely sensitive to ACGs with a 50% inhibitory concentration (IC50) value of 0.26 ng/mL, a very encouraging discovery. ACGs-NPs demonstrated very good dose-dependent antitumor efficacy in a broad range of 45?1200 μg/kg on JEG-3 tumor-bearing mice. At a very low dose (1200 μg/kg), ACGs-NPs achieved a high tumor inhibition rate (TIR) of 77.6% through oral administration, displaying a significant advantage over paclitaxel (PTX) injections that are currently used as first-line anti-choriocarcinoma drugs. In the acute toxicity study, the half lethal dose (LD50) of ACGs-NPs was 135.5 mg/kg, which was over 100 times as of the effective antitumor dose, indicating good safety of ACGs-NPs. ACGs-NPs show promise as a new type of and potent anti-choriocarcinoma drug in the future. more...
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- 2021
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7. Treatment of low-risk gestational trophoblastic neoplasia
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Matthew C. Winter
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Disease ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Gestational Trophoblastic Disease ,Retrospective Studies ,Chemotherapy ,030219 obstetrics & reproductive medicine ,business.industry ,Choriocarcinoma ,Obstetrics and Gynecology ,Combination chemotherapy ,General Medicine ,medicine.disease ,Methotrexate ,Clinical research ,chemistry ,030220 oncology & carcinogenesis ,Dactinomycin ,Female ,Gestational trophoblastic neoplasia ,business ,medicine.drug - Abstract
Low-risk gestational trophoblastic neoplasia (GTN), defined as FIGO/WHO score 0-6, is highly curable with an overall survival rate, which is approximately 100%. For most low-risk GTN patients, first-line single-agent chemotherapy with either methotrexate or actinomycin-D is recommended with overall complete human chorionic gonadotrophin (hCG) response rates of 60%-90% in mostly retrospective, non-randomised studies. The few randomised trials that exist are not appropriately powered or designed to define the optimal first-line treatment. Approximately 25%-30% of low-risk patients will develop resistance to initial single-agent chemotherapy with an increase in the FIGO score, a diagnosis of choriocarcinoma, higher pre-treatment hCG and the presence of metastatic disease being associated with an increase in the risk of resistance. The optimal treatment of patients scoring WHO 5 and 6 remains poorly defined given that approximately 70%-80% of these patients develop resistance to first-line single-agent chemotherapy, and there is an urgent need to refine the FIGO/WHO scoring system so that these patients can be identified for more intensive therapy from the outset. Despite this, almost all low-risk patients who experience treatment failure with first-line monotherapy will be cured with either sequential single-agent chemotherapy or multiagent chemotherapy with or without surgery. Given the associated increased short and longer-term toxicities associated with multi-agent chemotherapy, promising strategies to reduce the exposure of women to combination chemotherapy in low-risk disease have been investigated, including the use of carboplatin and immune check-point inhibitors. Further evaluation is required to define optimal patient selection, particularly with the use of immunotherapeutic agents given their significant increased costs and lack of longer-term safety data. Although there is a clear need to revise the FIGO/WHO (2000) scoring system, consistent international use of this is recommended to facilitate the comparison of data along with future focus in the development of international collaborative translational and clinical research, including randomised controlled trials. more...
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- 2021
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8. Insulin reverses choriocarcinoma 5- fluorouracil resistance
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Ying Shan, Cui Jiang, Yanyi Li, Huanmei Sun, Jiachang Hu, Hongyu Han, Jianglong Zhu, and Hu Zhang
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0301 basic medicine ,insulin ,medicine.medical_treatment ,Mice, Nude ,Bioengineering ,Applied Microbiology and Biotechnology ,Flow cytometry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Pregnancy ,Cell Line, Tumor ,Survivin ,medicine ,Animals ,Humans ,Viability assay ,Choriocarcinoma ,5-FU ,medicine.diagnostic_test ,Cell growth ,Chemistry ,Insulin ,chemoresistance ,General Medicine ,medicine.disease ,030104 developmental biology ,Apoptosis ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cancer research ,Female ,Fluorouracil ,TP248.13-248.65 ,Biotechnology ,Research Article ,Research Paper - Abstract
Choriocarcinoma (CC) is a gestational trophoblastic tumor secondary to a gravid or non-gravid pregnancy. It is characterized by rapid growth, high invasion, and high metastatic potential and chemotherapy resistance that significantly affect survival rate of CC patients. Insulin is implicated in alleviation of chemotherapy resistance in CC. However, the mechanism of reversing resistance in CC has not been explored. Our purpose was to explore insulin effect on 5-fluorouracil (5-FU) resistance in CC and elucidate its potential mechanism in vitro and in vivo. CKK-8, colony formation, Transwell, and flow cytometry were used to detect the effect of insulin on 5-FU resistance in CC cells JEG-3 and JARS. Xenograft mice were used to evaluate the effect of insulin on 5-FU resistance. Results showed that insulin combined with 5-FU suppressed cell viability by 30% in JEG-3 and 43% in JAR compared with 5-FU alone in 72 h. What’s more, insulin combined with 5-FU promoted cell apoptosis, inhibited cell proliferation, migration, and phosphorylation of survivin at residue threonine 34 (Thr34) and drug resistance-related proteins, P-GP and MRP1 levels (p more...
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- 2021
9. Neonatal Malignant Disorders
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Christopher B. Weldon, Brent R. Weil, A. Lindsay Frazier, James F. Amatruda, and Rachana Shah
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medicine.medical_specialty ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Choriocarcinoma ,Obstetrics and Gynecology ,Disease ,medicine.disease ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030225 pediatrics ,Fetus in fetu ,Pediatrics, Perinatology and Child Health ,Biopsy ,medicine ,030212 general & internal medicine ,Germ cell tumors ,Radiology ,Teratoma ,business - Abstract
Germ cell tumors (GCTs) comprise a wide spectrum of benign and malignant tumors. Neonatal GCTs are predominantly teratomas (mature or immature), which are typically cured with surgery alone. Relapses are infrequent even in the setting of microscopic residual disease; therefore, negative surgical margins at the cost of significant morbidity are not recommended. In neonates with metastatic malignant disease or malignant disease for which upfront surgical resection is not feasible without significant morbidity, an initial biopsy followed by neoadjuvant chemotherapy and delayed surgical resection is recommended. Carboplatin-based regimens should be considered when chemotherapy is indicated. more...
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- 2021
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10. Genistein inhibits the proliferation of human choriocarcinoma cells via the downregulation of estrogen receptor-α phosphorylation at serine 118
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Edi Hartoyo, Hariadi Yuseran, Tatit Nurseta, and Handono Kalim
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Confluency ,Nutrition and Dietetics ,Nutrition. Foods and food supply ,Cell growth ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Choriocarcinoma ,Trophoblast ,Malignancy ,Genistein ,Estrogen receptor ,Cell cycle ,medicine.disease ,chemistry.chemical_compound ,chemistry ,Downregulation and upregulation ,Estrogen ,medicine ,Cancer research ,TX341-641 - Abstract
Summary: Background & aims: Choriocarcinoma is a malignant trophoblastic tumor. The phosphorylation of estrogen receptor-α at serine 118 (p-ER-s118) decreases cancer cell proliferation. However, the effect of genistein as a modulator of p-ER-s118 and proliferation of chorioarcinoma cells remains to be understood. This study aims at determining the function of genistein on p-ER-s118 levels and human choriocarcinoma JEG-3 cell proliferation. Methods: After reaching confluency, cells were divided into six groups, the control group (without methyl-piperidino-pyrazole (MPP) pre-treatment and genistein treatment); and groups with cells treated with genistein at concentrations of 0, 10, 25, 50, and 100 μM (cells were pretreated with MPP). Expression of p-ER-s118 and Ki-67 were analyzed using immunocytochemistry. Results: Different doses of genistein decreased p-ER-s118 levels compared to those in the control (p more...
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- 2021
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11. Reduction of pl-CSA through ChSy-2 knockout inhibits tumorigenesis and metastasis of choriocarcinoma in JEG3 cells
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Shiling Chen, Baobei Wang, Tianxia Xiao, Xiujun Fan, Zhang Juzuo, Jian Zhang, Chen Zhilong, and Jie Chen
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Carcinogenesis ,medicine.disease_cause ,Flow cytometry ,Metastasis ,Mice ,Cell Movement ,Pregnancy ,In vivo ,Cell Line, Tumor ,choriocarcinoma ,medicine ,Animals ,Humans ,Cell Proliferation ,medicine.diagnostic_test ,Chemistry ,Cell growth ,Chondroitin Sulfates ,Choriocarcinoma ,Glycosyltransferases ,Membrane Proteins ,ChSy-2/pl-CSA ,General Medicine ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Specific Pathogen-Free Organisms ,tumorigenesis ,Cell culture ,Gene Knockdown Techniques ,Uterine Neoplasms ,Cancer research ,Female ,molecular therapy ,Research Paper - Abstract
Background: Placental-like chondroitin sulfate A (pl-CSA) is exclusively expressed in cancerous and placental tissues and is highly correlated with the degree of malignancy. However, the mechanism through which pl-CSA regulates tumorigenesis and metastasis in choriocarcinoma remains unclear. Methods: Stable transfectants of the JEG3 choriocarcinoma cell line, including a negative control (NC) line and a cell line with knockout of the biosynthetic enzyme CS synthase-2 (ChSy-2) (ChSy-2-/-), were obtained using CRISPR/Cas9 systems and identified by immunofluorescence, flow cytometry, western blots and enzyme-linked immunosorbent assays (ELISAs). The proliferation, migration, invasion and colony formation of the cells were determined by a cell counting kit, scratch-wound assays, transwell assays and soft agar colony formation assays in vitro, respectively. The tumorigenesis and metastasis of choriocarcinoma were also investigated through two xenograft models in vivo. Results: The ChSy-2 protein in the ChSy-2-/-group was below the detection threshold, which was accompanied a significant reduction in the pl-CSA level. Reducing pl-CSA through ChSy-2 knockout significantly inhibited cell proliferation, migration, invasion and colony formation in vitro and tumorigenesis and metastasis of choriocarcinoma, with deceases in tumor volume and metastatic foci and a high percent survival compared to the NC in vivo. Conclusion: pl-CSA, as a necessary component of JEG-3 cells, was efficiently reduced through ChSy-2 knockout, which significantly inhibited the tumorigenesis and metastasis of choriocarcinoma. ChSy-2/pl-CSA could be alternative targets for tumor therapy. more...
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- 2021
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12. SLAMF1 Promotes Methotrexate Resistance via Activating Autophagy in Choriocarcinoma Cells
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Yu Zhang, Dazun Shi, and Yan Tian
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0301 basic medicine ,musculoskeletal diseases ,autophagy ,methotrexate ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,immune system diseases ,medicine ,choriocarcinoma ,heterocyclic compounds ,Viability assay ,Cytotoxicity ,skin and connective tissue diseases ,Original Research ,drug resistance ,Chemistry ,Autophagy ,Choriocarcinoma ,medicine.disease ,030104 developmental biology ,Oncology ,Cancer Management and Research ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,Methotrexate ,SLAMF1 ,medicine.drug - Abstract
Dazun Shi, Yu Zhang, Yan Tian Department of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Yan TianDepartment of Gynecology and Obstetrics, Xiangya Hospital, Central South University, Changsha 410008, People’s Republic of ChinaEmail tianyxycsu@163.comObjective: The acquisition of chemoresistance to methotrexate (MTX) still remains one of the major challenges for choriocarcinoma treatment. Herein, we aimed to evaluate the potential role of Signaling Lymphocytic Activation Molecule Family Member 1 (SLAMF1) as a possible regulator of chemoresistance to MTX in choriocarcinoma.Material and Methods: MTX-resistant JEG3 and JAR sublines (JEG3/MTX, JAR/MTX) were used to study SLAMF1 function. CCK8 assay and soft agar assay were conducted to measure the cell viability and clonogenesis of choriocarcinoma cells, respectively; MDC incorporation assay was conducted for the quantification of intracellular autophagy; BrdU labeling was used to assess the proliferative potential of choriocarcinoma cells; SLAMF1 protein expression was analyzed by Western blotting.Results: Upregulation of SLAMF1 expression was observed in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental JEG3 and JAR cell lines, respectively. Knockdown of SLAMF1 markedly attenuated cell viability and soft agar clonogenesis after incubation with MTX in JEG3/MTX and JAR/MTX cells. In contrast, constitutive expression of SLAMF1 rescued cell survival soft agar clonogenesis in JEG3 and JAR cells treated with MTX. Moreover, autophagy is apparently activated in MTX-resistant JEG3/MTX and JAR/MTX sublines compared to their parental cell lines. Autophagy inhibitor 3-methyladenine and bafilomycin A1 enhanced MTX-induced cytotoxicity in MTX-resistant JEG3 and JAR sublines. Further, SLAMF1 might activate autophagy-related mechanism to promote resistance to MTX in choriocarcinoma cells. Depletion of SLAMF1 suppressed autophagy and induced apoptosis in MTX-treated JEG3/MTX and JAR/MTX cells.Conclusion: SLAMF1 might promote MTX resistance via activating protective autophagy in choriocarcinoma cell lines. Targeting SLAMF1 might be a useful therapeutic strategy to sensitize choriocarcinoma cells to MTX-based regimens.Keywords: choriocarcinoma, methotrexate, drug resistance, SLAMF1, autophagy more...
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- 2020
13. Tumor-suppressive function of methiothepin in human placental choriocarcinoma cells
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Jin Young Lee, Gwonhwa Song, and Whasun Lim
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0301 basic medicine ,Embryology ,MAP Kinase Signaling System ,Methiothepin ,Trophoblastic Tumor ,Apoptosis ,Oxidative phosphorylation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Cell Movement ,Pregnancy ,Tumor Cells, Cultured ,Humans ,Endocrine system ,Serotonin receptor antagonist ,Choriocarcinoma ,Cell Proliferation ,Membrane Potential, Mitochondrial ,030219 obstetrics & reproductive medicine ,Chemistry ,Endoplasmic reticulum ,Obstetrics and Gynecology ,Placentation ,Cell Biology ,Mitochondria ,030104 developmental biology ,Reproductive Medicine ,Paclitaxel ,Uterine Neoplasms ,Cancer research ,Female ,Serotonin Antagonists ,Serotonin ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt - Abstract
Placental choriocarcinoma is a malignant trophoblastic tumor associated with placentation. During placentation, complicated molecular networks are mediated by endocrine and paracrine signals. Serotonin neurotransmitters have been identified in the transmembrane region of human placental choriocarcinoma (HPC) cells as tumor promoters; therefore, their antagonists have anti-cancer properties. Although methiothepin, a serotonin receptor antagonist and FDA-approved psychotropic agent, has shown multi-pharmacological functions in various disease models, its anti-tumorigenic activity and mechanisms underlying its action against HPC are unknown. Therefore, we identified the anti-cancer effects of methiothepin in JEG3 and JAR HPC cells. Methiothepin attenuated mitochondrial function and induced endoplasmic reticular stress, reducing oxidative phosphorylation and causing metabolic shifting in HPC cells. Furthermore, methiothepin showed synergistic pharmacological effects with paclitaxel in HPC cells. Our results highlight the robust tumor-suppressive function of methiothepin in HPC. Our findings provide new insights into the repositioning of methiothepin from a psychotropic agent to novel anti-cancer agents, especially against HPC. more...
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- 2020
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14. Crosstalk between estradiol and NFκB signaling pathways on placental leptin expression
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Roberto Casale, Antonio Pérez-Pérez, Julieta Maymó, Maria Fernanda Camisay, Cecilia L. Varone, Alejandra G. Erlejman, Malena Schanton, and Víctor Sánchez-Margalet
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Leptin ,0301 basic medicine ,Leptin expression ,Embryology ,placenta ,Placenta ,Estrogen receptor ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Downregulation and upregulation ,Pregnancy ,estradiol ,Humans ,Choriocarcinoma ,NF-kB ,Phosphorylation ,Autocrine signalling ,Transcription factor ,Cell Nucleus ,030219 obstetrics & reproductive medicine ,Chemistry ,NF-kappa B ,Obstetrics and Gynecology ,Estrogens ,purl.org/becyt/ford/3.1 [https] ,Cell Biology ,Cell biology ,IκBα ,030104 developmental biology ,Receptors, Estrogen ,Reproductive Medicine ,Uterine Neoplasms ,Female ,purl.org/becyt/ford/3 [https] ,Signal transduction ,Estrogen receptor alpha ,signal transduction ,hormones, hormone substitutes, and hormone antagonists - Abstract
Pregnancy success requires a proper fetal maternal interaction at the establishment of implantation. Leptin has been described as a multitasking cytokine in pregnancy, particularly in the placenta, where it acts as an autocrine hormone. The expression of leptin in normal trophoblastic cells is regulated by different endogenous signals. We have previously reported that 17β-estradiol upregulates placental leptin expression through genomic and non-genomic mechanisms. To improve the knowledge of estrogen receptor mechanisms in regulating leptin gene expression, we examined transcription nuclear factor kappa B (NFκB) effect on estradiol leptin induction in human BeWo cell line and human term placental explants. We demonstrated that estradiol induction effect on leptin expression is blocked by the inhibition of NFκB signaling. We also found that the overexpression of p65 subunit, the active form of NFκB, induces leptin expression. Moreover, downregulation of estrogen receptor alpha (ERα), through a specific siRNA, abolished NFκB effect on leptin expression. We also demonstrated that ERα enhanced NFκB signaling pathway activation in trophoblastic cells. Estradiol treatment significantly increased p65 expression and phosphorylation of the inhibitory protein κB alpha (IκBα). A reporter plasmid containing NFκB elements was also induced in response to estradiol stimulation. Localization experiments revealed that estradiol treatment induced nuclear localization of overexpressed p65. Moreover, the overexpression of ERα produced a complete displacement of p65 protein to the nucleus. Finally, immunoprecipitation experiments showed the presence of a complex containing ERα and NFκB. All these evidences suggest a cooperative behavior between ERα and NFκB transcription factors to induce leptin transcription. Fil: Schanton, Malena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Maymo, Julieta Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Camisay, Maria Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Pérez Pérez, Antonio. Universidad de Sevilla; España. Hospital Universitario Virgen Macarena; España Fil: Casale, Roberto. Hospital Nacional Profesor Alejandro Posadas; Argentina Fil: Sanchez Margalet, Victor. Universidad de Sevilla; España Fil: Erlejman, Alejandra Giselle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Varone, Cecilia Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina more...
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- 2020
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15. Activated α2-macroglobulin binding to cell surface GRP78 induces trophoblastic cell fusion
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Daniel Bastida-Ruiz, Salvatore V. Pizzo, Christine Wuillemin, Marie Cohen, Michal Yaron, Aude Pederencino, and Begoña Martinez de Tejada
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0301 basic medicine ,Cell biology ,MAP Kinase Signaling System ,Cell ,Down-Regulation ,lcsh:Medicine ,Article ,Cell Line ,Cell Fusion ,03 medical and health sciences ,0302 clinical medicine ,Syncytiotrophoblast ,Downregulation and upregulation ,Pregnancy ,Developmental biology ,medicine ,Humans ,alpha-Macroglobulins ,Choriocarcinoma ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,lcsh:Science ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Multidisciplinary ,Cell fusion ,ddc:618 ,Chemistry ,lcsh:R ,Placentation ,Trophoblasts ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,embryonic structures ,Unfolded protein response ,Unfolded Protein Response ,Female ,lcsh:Q ,Signal transduction ,Signal Transduction - Abstract
The villous cytotrophoblastic cells have the ability to fuse and differentiate, forming the syncytiotrophoblast (STB). The syncytialisation process is essential for placentation. Nevertheless, the mechanisms involved in cell fusion and differentiation are yet to be fully elucidated. It has been suggested that cell surface glucose-regulated protein 78 (GRP78) was involved in this process. In multiple cancer cells, cell membrane-located GRP78 has been reported to act as a receptor binding to the active form of α2-macroglobulin (α2M*), activating thus several cellular signalling pathways implicated in cell growth and survival. We hypothesised that GRP78 interaction with α2M* may also activate signalling pathways in trophoblastic cells, which, in turn, may promote cell fusion. Here, we observed that α2M mRNA is highly expressed in trophoblastic cells, whereas it is not expressed in the choriocarcinoma cell line BeWo. We thus took advantage of forskolin-induced syncytialisation of BeWo cells to study the effect of exogenous α2M* on syncytialisation. We first demonstrated that α2M* induced trophoblastic cell fusion. This effect is dependent on α2M*-GRP78 interaction, ERK1/2 and CREB phosphorylation, and unfolded protein response (UPR) activation. Overall, these data provide novel insights into the signalling molecules and mechanisms regulating trophoblastic cell fusion. more...
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- 2020
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16. α,β-Thujone suppresses human placental choriocarcinoma cells via metabolic disruption
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Hahyun Park, Gwonhwa Song, Whasun Lim, and Jin Young Lee
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0301 basic medicine ,Embryology ,Cell Survival ,Placenta ,Apoptosis ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Pregnancy ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Sensitization ,Bicyclic Monoterpenes ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Calcium metabolism ,030219 obstetrics & reproductive medicine ,Chemistry ,Obstetrics and Gynecology ,Depolarization ,Cell Biology ,medicine.disease ,Mitochondria ,030104 developmental biology ,medicine.anatomical_structure ,Reproductive Medicine ,Paclitaxel ,Cell culture ,Uterine Neoplasms ,embryonic structures ,Unfolded protein response ,Calcium ,Female ,Signal Transduction - Abstract
α,β-Thujone is a natural terpenoid found in many medicinal herbs, such as Artemisia absinthium (wormwood), that exhibits antioxidant, anti-diabetic, and anti-tumorigenic effects. α,β-Thujone has numerous functions; it serves as a food ingredient, cosmetic additive, and medicinal remedy. Although the therapeutic properties of α,β-thujone were previously revealed, a comprehensive description of the mechanisms of its anti-cancer potential in choriocarcinoma is yet to be provided. To our knowledge, this study is the first to demonstrate that α,β-thujone attenuates JEG3 and JAR choriocarcinoma cells through a caspase-dependent intrinsic apoptotic pathway. Moreover, α,β-thujone was demonstrated to induce a global mitochondrial defect and ER stress in choriocarcinoma by causing mitochondrial depolarization, calcium overload, and metabolic alterations, thereby leading to energy deprivation, which eventually contributes to the increase in apoptosis of choriocarcinoma cells. Herein, we also revealed the synergistic anti-cancer activity of α,β-thujone via its sensitization effect on paclitaxel in choriocarcinoma cells. Altogether, our findings suggest that α,β-thujone is a novel, natural pharmacological compound that can be used to treat human placental choriocarcinoma. more...
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- 2020
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17. PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation
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Diana Barea Roldan, Christoph Rohde, Christoph Hartmann, Ugur Sahin, Michael Koslowski, Tim Beißert, Giuseppe Cagna, Stefanie Hubich-Rau, Claudia Paret, Özlem Türeci, Matthias Grimmler, and Stefan Wöll more...
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0301 basic medicine ,Chemistry ,extracellular matrix ,AKT ,Choriocarcinoma ,Motility ,Fibroblast growth factor ,medicine.disease ,medicine.disease_cause ,tumorigenesis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,PLAC1 ,Oncology ,030220 oncology & carcinogenesis ,fibroblast growth factor ,medicine ,Cancer research ,Secretion ,Receptor ,Carcinogenesis ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Research Paper - Abstract
PLAC1 (placenta enriched 1) is a mammalian trophoblast-specific protein. Aberrant expression of PLAC1 is observed in various human cancers, where it is involved in the motility, migration, and invasion of tumor cells, which are associated with the phosphoinositide 3-kinase (PI3K)/AKT pathway. We previously demonstrated that AKT activation mediates the downstream effects of PLAC1; however, the molecular mechanisms of PLAC1-induced AKT-mediated tumor-related processes are unclear. We studied human choriocarcinoma and breast cancer cell lines to explore the localization and receptor-ligand interactions, as well as the downstream effects of PLAC1. We show secretion and adherence of PLAC1 to the extracellular matrix, where it forms a trimeric complex with fibroblast growth factor 7 (FGF7) and its receptor, FGF receptor 2 IIIb (FGFR2IIIb). We further show that PLAC1 signaling via FGFR2IIIb activates AKT phosphorylation in cancer cell lines. As the FGF pathway is of major interest in anticancer therapeutic strategies, these data further promote PLAC1 as a promising anticancer drug target. more...
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- 2020
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18. Cell surface membrane lysosome-associated membrane glycoprotein 2 promotes cell adhesion via abundant N-glycans in choriocarcinoma
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Hiroaki Kajiyama, Yukari Oda, Kimihiro Nishino, Yuki Nishiko, Eiko Yamamoto, Eri Watanabe, Kaoru Niimi, and Mayu Shibata
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Glycan ,Galectins ,Mice ,Polysaccharides ,Cell Line, Tumor ,Lysosomal-Associated Membrane Protein 2 ,medicine ,Cell Adhesion ,Animals ,Humans ,Neoplasm Invasiveness ,Choriocarcinoma ,Cell adhesion ,biology ,Chemistry ,Cell Membrane ,Obstetrics and Gynecology ,Lysosome-Associated Membrane Glycoprotein 2 ,medicine.disease ,Cell biology ,Extracellular Matrix ,Reproductive Medicine ,biology.protein ,Cell surface membrane ,Developmental Biology - Abstract
Lysosome-associated membrane glycoprotein 2 (LAMP-2) is a target protein for glycosylation by N-acetylglucosaminyltransferase IV (GnT-IV), which catalyzes the formation of β1,4GlcNAc branches on the mannose core of N-glycans in choriocarcinoma cells. However, the role of LAMP-2, especially when it is expressed in the cell surface membrane of choriocarcinoma cells, has not been well investigated in the progression of choriocarcinoma. This study aimed to elucidate the function of the cell surface membrane LAMP-2 in the malignancy of choriocarcinoma.We evaluated the localization of LAMP-2 in some choriocarcinoma cell lines and clinical samples of choriocarcinoma, normal placenta, hydatidiform mole, and invasive mole by flow cytometry, immunocytochemistry, and immunohistochemistry. We performed functional experiments using the knockout or overexpression model of LAMP-2 in the presence or absence of galectins.LAMP-2 was observed in the cell surface membrane of some choriocarcinoma cell lines and tumor cells of choriocarcinoma tissue and trophoblasts of the placenta, hydatidiform mole, and invasive mole. Cell surface membrane LAMP-2 knockout decreased cell adhesion and invasion in choriocarcinoma cells. Conversely, cell surface membrane LAMP-2A overexpression increased cell adhesion and invasion. Experiments in the presence of galectins revealed that abundant N-glycans bound to the peptide core of the luminal side of the cell surface membrane LAMP-2 mediated cell adhesion of choriocarcinoma cells by interacting with galectins in the extracellular matrix (ECM).Cell surface membrane LAMP-2, which is glycosylated by GnT-IV, contributes to the malignancy of choriocarcinoma by promoting cell adhesion with the ECM via abundant N-glycans. more...
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- 2021
19. Macrophage migration inhibitory factor is differentially expressed in normal and choriocarcinoma trophoblast cells
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Z Bojic-Trbojevic, M. Jovanović Krivokuća, Aleksandra Vilotić, and Ljiljana Vićovac
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Cancer Research ,Cell type ,CD74 ,medicine.medical_treatment ,Receptors, Interleukin-8B ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Receptor ,Macrophage Migration-Inhibitory Factors ,reproductive and urinary physiology ,Chemistry ,Histocompatibility Antigens Class II ,Trophoblast ,medicine.disease ,Molecular biology ,female genital diseases and pregnancy complications ,Trophoblasts ,3. Good health ,Antigens, Differentiation, B-Lymphocyte ,Intramolecular Oxidoreductases ,medicine.anatomical_structure ,Cytokine ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,embryonic structures ,Female ,Macrophage migration inhibitory factor - Abstract
Trophoblast cells are specific for placenta, the organ necessary for development of the fetus. Trophoblast derived choriocarcinoma is a rare cancer, with high metastatic potential, invading surrounding tissues and distant organs. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in a wide range of biological processes, which is increased in almost all human cancers. Expression of MIF in normal and choriocarcinoma trophoblast cells is investigated here, using normal extravillous trophoblast derived cell line HTR-8/SVneo, and choriocarcinoma cell lines JAR and JEG3. Expression of MIF and its receptors CD74 and CXCR2 was investigated at mRNA level using qPCR. Expression of MIF protein was studied using immunofluorescence and western blot, under reducing and native conditions, in whole cell lysates, subcellular fractions and conditioned media. The expression of MIF mRNA was similar in all three cell lines, while CD74 mRNA was more expressed in choriocarcinoma cells (14-fold for JAR, 12-fold for JEG3, p0.01). CXCR2 mRNA was higher in JEG3 cell line compared to HTR-8/SVneo cells (6-fold, p0.01). While the cellular level of MIF was similar, the level of secreted MIF was lower in JAR cell conditioned media compared to media of both HTR-8/SVneo (2.8-fold, p0.01) and JEG3 cells (4.1-fold, p0.001). Cellular distribution of MIF was similar between the studied cell types. MIF was predominantly cytoplasmic, but also detected in membrane, nuclear soluble and nuclear chromatin fraction. MIF appeared in high molecular weight complexes of150 kDa under native conditions. A band of 140-145 kDa was consistently present in JEG3 cell lysates, while it was absent or very weak in other cell types. These results show that MIF/CD74 axis is shifted in choriocarcinoma, as previously shown for other cancers, and further justifies research towards the most effective MIF targeting therapeutics. more...
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- 2020
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20. Acrylonitrile induced cell cycle arrest and apoptosis by promoting the formation of reactive oxygen species in human choriocarcinoma cells
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Kyung-Chul Choi and Soo-Min Kim
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Cyclin-Dependent Kinase Inhibitor p21 ,Cell cycle checkpoint ,Cyclin E ,Cyclin D ,Gene Expression ,Apoptosis ,010501 environmental sciences ,Toxicology ,030226 pharmacology & pharmacy ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Humans ,Choriocarcinoma ,Viability assay ,0105 earth and related environmental sciences ,chemistry.chemical_classification ,Reactive oxygen species ,Acrylonitrile ,Dose-Response Relationship, Drug ,biology ,Cell growth ,Chemistry ,Cell Cycle Checkpoints ,Molecular biology ,embryonic structures ,Cancer cell ,biology.protein ,Tumor Suppressor Protein p53 ,Reactive Oxygen Species - Abstract
Acrylonitrile (AN), which is widely utilized in the manufacture of plastics, acrylamide, acrylic fibers, and resins, is also one of main components of cigarette smoke (CS). In this study, we examined the effects of AN on the cell viability and apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cell lines. A cell viability assay confirmed that AN decreased the cell proliferation of JEG-3 and BeWo cells in a dose-dependent manner. Additionally, Western blot assay revealed that protein expression of cyclin D and cyclin E decreased, while protein expression of p21 and p27 increased in response to AN treatment for 48 hr. The changes in reactive oxygen species (ROS) levels in JEG-3 and BeWo cells exposed to AN were also measured by a dichlorofluorescein diacetate (DCFH-DA) assay, which revealed that ROS levels increased in response to AN treatment for 48 hr. Moreover, western blot assay confirmed that AN treatment of JEG-3 and BeWo cells for 4 hr promoted the expression of phosphorylated eukaryotic initiation factor 2 alpha protein (p-eIF2α), C/EBP homologous protein (CHOP) and caspase 12, which are known to be involved in ROS-mediated endoplasmic reticulum stress (ER-stress)-related apoptosis. Overall, the protein expression of p53 and Bax (a pro-apoptosis marker) increased, while the expression of Bcl-xl (an anti-apoptotic marker) decreased and the number of apoptotic cells increased in response to AN treatment for 48 hr. Taken together, these results suggest that AN has the potential to induce apoptosis of JEG-3 and BeWo human choriocarcinoma cancer cells by activating ROS. more...
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- 2020
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21. Changes in Vasodilator-Stimulated Phosphoprotein Phosphorylation, Profilin-1, and Cofilin-1 in Accreta and Protection by DHA
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Mehboob Ali, Catalin S. Buhimschi, Kathryn M. Heyob, Irina A. Buhimschi, and Lynette K. Rogers
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Cofilin 1 ,0301 basic medicine ,Docosahexaenoic Acids ,genetic structures ,Placenta ,Cell ,Apoptosis ,Placenta Accreta ,macromolecular substances ,Profilins ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Pregnancy ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Actin-binding protein ,Phosphorylation ,Cell Proliferation ,030219 obstetrics & reproductive medicine ,biology ,Chemistry ,Microfilament Proteins ,Vasodilator-stimulated phosphoprotein ,Obstetrics and Gynecology ,Trophoblast ,Original Articles ,Phosphoproteins ,medicine.disease ,Trophoblasts ,030104 developmental biology ,medicine.anatomical_structure ,Phosphoprotein ,embryonic structures ,Cancer research ,biology.protein ,Female ,Cell Adhesion Molecules - Abstract
Accreta and gestational trophoblastic disease (ie, choriocarcinoma) are placental pathologies characterized by hyperproliferative and invasive trophoblasts. Cellular proliferation, migration, and invasion are heavily controlled by actin-binding protein (ABP)-mediated actin dynamics. The ABP vasodilator-stimulated phosphoprotein (VASP) carries key regulatory role. Profilin-1, cofilin-1, and VASP phosphorylated at Ser157 (pVASP-S157) and Ser239 (pVASP-S239) are ABPs that regulate actin polymerization and stabilization and facilitate cell metastases. Docosahexaenoic acid (DHA) inhibits cancer cell migration and proliferation. We hypothesized that analogous to malignant cells, ABPs regulate these processes in extravillous trophoblasts (EVTs), which exhibit aberrant expression in placenta accreta. Placental–myometrial junction biopsies of histologically confirmed placenta accreta had significantly increased immunostaining levels of cofilin-1, VASP, pVASP-S239, and F-actin. Treatment of choriocarcinoma-derived trophoblast (BeWo) cells with DHA (30 µM) for 24 hours significantly suppressed proliferation, migration, and pVASP-S239 levels and altered protein profiles consistent with increased apoptosis. We concluded that in accreta changes in the ABP expression profile were a response to restore homeostasis by counteracting the hyperproliferative and invasive phenotype of the EVT. The observed association between VASP phosphorylation, apoptosis, and trophoblast proliferation and migration suggest that DHA may offer a therapeutic solution for conditions where EVT is hyperinvasive. more...
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- 2019
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22. Lapatinib Inhibits Amphiregulin-induced BeWo Choriocarcinoma Cell Proliferation by Reducing ERK1/2 and AKT Signaling Pathways
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Lolita Schneider Pizzolato, Leticia Vicosa Pires, Jung-Chien Cheng, Ilma Simoni Brum, Yuyin Yi, E. A. A. Cordero, and Peter C.K. Leung
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Cancer Research ,MAP Kinase Signaling System ,Receptor, ErbB-2 ,Apoptosis ,Lapatinib ,Amphiregulin ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Epidermal growth factor receptor ,skin and connective tissue diseases ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,biology ,Cell growth ,Chemistry ,General Medicine ,medicine.disease ,ErbB Receptors ,Gene Expression Regulation, Neoplastic ,Oncogene Protein v-akt ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,biology.protein ,Female ,Signal transduction ,medicine.drug - Abstract
Background Human choriocarcinoma is the most aggressive type of gestational trophoblastic neoplasia. The expression of epidermal growth factor receptor (EGFR) in choriocarcinomas is significantly higher than those of trophoblastic cells in healthy placentas. Lapatinib is a potent EGFR and human epidermal growth factor receptor 2 (HER2) inhibitor that inhibits cell proliferation and induces apoptosis in various human cancer cells. Amphiregulin (AREG) is the most abundant EGFR ligand in amniotic fluid during human pregnancy. Aim To explore the role of AREG in human choriocarcinoma cell proliferation. Materials and methods The effect of lapatinib and AREG on cell proliferation was examined by the MTT assay. Western blots were used to investigate EGFR and HER2 expression, and the activation of caspase-3, extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT) signaling pathways. Results Treatment with lapatinib reduced BeWo cell proliferation by inducing apoptosis. Moreover, AREG treatment stimulated BeWo cell proliferation by activating ERK1/2 and PI3K/AKT signaling pathways, which was blocked by lapatinib. Conclusion Targeting EGFR/HER2 might be a useful therapeutic strategy for human choriocarcinoma. more...
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- 2019
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23. Long noncoding RNA H19 promotes chemotherapy resistance in choriocarcinoma cells
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Huining Liu, Shuran Yu, Qianxia Tan, and Chenchun Wu
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0301 basic medicine ,Cell Survival ,Apoptosis ,Drug resistance ,Biochemistry ,Inhibitory Concentration 50 ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Choriocarcinoma ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Wound Healing ,Messenger RNA ,Chemistry ,TOR Serine-Threonine Kinases ,Cell Biology ,medicine.disease ,female genital diseases and pregnancy complications ,Gene Expression Regulation, Neoplastic ,Methotrexate ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cell culture ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,Phosphorylation ,RNA, Long Noncoding ,Fluorouracil ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Choriocarcinoma (CC) is a trophoblast tumor prone to early distant organ metastases. At present, the main treatment for CC is chemotherapy, but chemotherapy resistance readily occurs and leads to treatment failure. H19 is a long noncoding RNA, and its abnormal expression has been found in various tumors, including CC. H19 is also considered to be related to the drug resistance mechanism of the same cancers. To investigate the role of H19 in drug-resistant CC cells, the following experiments were designed. We used human CC cell line JEG-3 to establish cell lines resistant to methotrexate and 5-fluorouracil (JEG-3/MTX and JEG-3/5-FU) and detected the expression of H19 in JEG-3, JEG-3/MTX, JEG-3/5-FU cells, JEG-3 with MTX, and JEG-3 with 5-FU. We found that the expression of H19 in the JEG-3/MTX and JEG-3/5-FU cells were significantly higher than that in JEG-3 cells. JEG-3 cells were treated with MTX or 5-FU for and quantitative real-time polymerase chain reaction assay revealed that H19 messenger RNA expression increased. Furthermore, after H19 was knocked out, the drug resistance index of the JEG-3/MTX and JEG-3/5-FU cells decreased; the proliferation, migration, and invasion ability diminished significantly; and apoptosis increased significantly. Finally, we detected the total and phosphorylation protein expression of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) in the JEG-3/MTX and JEG-3/5-FU cells. The total protein of PI3K, AKT, and mTOR in the H19 knockout resistant cells showed no significant change relative to those in the H19 non-knockout resistant cells, whereas the phosphorylated proteins of PI3K, AKT, and mTOR were significantly decreased. Phosphorylated proteins of PI3K, AKT, and mTOR in the JEG-3/MTX and JEG-3/5-FU cells were significantly higher than that in JEG-3 cells. After using inhibition of phosphorylated PI3K/AKT/mTOR, the proliferation, migration, and invasion ability of the JEG-3/MTX and JEG-3/5-FU cells diminished significantly; and apoptosis increased significantly. On the basis of the above experiments, we concluded that H19 is related to the drug resistance of CC, and the knockout of H19 can reduce the drug resistance of resistant CC cells; and decrease the proliferative, migratory, and invasive ability; and increase the apoptosis. PI3K/AKT/mTOR pathway might be involved in H19-mediated effects. H19 is expected to be a therapeutic target for the treatment of drug-resistant chorionic carcinoma. more...
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- 2019
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24. β-catenin/LIN28B promotes the proliferation of human choriocarcinoma cells via Let-7a repression
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Jing Wu, Hongbo Zhao, Baoxin Luan, Lanxiang Wu, Xuan Feng, Yan Du, Yinhua Yu, and Huandi Yu
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Small interfering RNA ,Trophoblastic Tumor ,Biophysics ,Biochemistry ,Pregnancy ,Cell Line, Tumor ,medicine ,Humans ,Gene silencing ,Choriocarcinoma ,Psychological repression ,beta Catenin ,reproductive and urinary physiology ,Cell Proliferation ,Gene knockdown ,Cell growth ,Chemistry ,RNA-Binding Proteins ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,Cell biology ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,Catenin ,Uterine Neoplasms ,embryonic structures ,Female ,RNA Interference ,Signal Transduction - Abstract
Choriocarcinoma is a rare and malignant trophoblastic tumor. However, the molecular mechanisms by which choriocarcinoma is regulated remain unknown. In the present study, we first elucidated that LIN28B was highly expressed in human choriocarcinoma tissues and choriocarcinoma cell lines. Our data further demonstrated that knockdown of LIN28B by small interfering RNA caused an increase in Let-7a expression in JAR cells. In addition, silencing of LIN28B inhibited IGF2BP1 expression and suppressed cell proliferation capacity, both of which can be markedly restored by Let-7a inhibitor. In contrast, LIN28B over-expression-improved cell proliferation was inhibited by Let-7a mimic. Knockdown of β-catenin resulted in reduced expression of LIN28B and increased expression of Let-7a. Knockdown of β-catenin also caused a decrease in cell proliferation, which can be recovered by re-expression of LIN28B or by Let-7a inhibitor. Collectively, our data indicate that β-catenin/LIN28B/Let-7a pathway may be crucial for the regulation of cell proliferation in human choriocarcinoma cells. more...
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- 2019
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25. An Overview of the Role of Long Non-Coding RNAs in Human Choriocarcinoma
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Ian Said-Huntingford, John J. O'Leary, Riccardo Di Fiore, Bridget Ellul, Duncan Ayers, James P Beirne, Mariela Vasileva-Slaveva, Maja Sabol, Antonio Giordano, Margarita Nikolova, Ana Félix, Sherif Suleiman, Sharon O'Toole, Jean Calleja-Agius, Petar Ozretić, Francesca Pentimalli, Mark Ward, Angel Yordanov, Stoyan Kostov, and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) more...
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Angiogenesis ,Carcinogenesis ,Disease ,Review ,Cancer -- Treatment ,lncRNA-based therapy ,Pregnancy ,Molecular Targeted Therapy ,Choriocarcinoma ,Biology (General) ,Spectroscopy ,long non-coding RNA ,rare cancer ,oncogenes or tumor suppressor genes ,General Medicine ,Long non-coding RNA ,Computer Science Applications ,Rare diseases ,Gene Expression Regulation, Neoplastic ,Chemistry ,medicine.anatomical_structure ,Molecular Diagnostic Techniques ,Uterine Neoplasms ,choriocarcinoma ,Female ,RNA, Long Noncoding ,Disease Susceptibility ,Antioncogenes ,Germ cell ,QH301-705.5 ,Catalysis ,Inorganic Chemistry ,Therapeutic approach ,Germline mutation ,SDG 3 - Good Health and Well-being ,medicine ,Biomarkers, Tumor ,Humans ,Physical and Theoretical Chemistry ,LncRNA-based therapy ,Oncogenes or tumor suppressor genes ,Rare cancer ,Molecular Biology ,QD1-999 ,Neoplasm Staging ,business.industry ,Organic Chemistry ,Cancer ,Basic Medical Sciences ,medicine.disease ,Cancer research ,Neoplasm Grading ,business - Abstract
Choriocarcinoma (CC), a subtype of trophoblastic disease, is a rare and highly aggressive neoplasm. There are two main CC subtypes: gestational and non-gestational, (so called when it develops as a component of a germ cell tumor or is related to a somatic mutation of a poorly differentiated carcinoma), each with very diverse biological activity. A therapeutic approach is highly effective in patients with early-stage CC. The advanced stage of the disease also has a good prognosis with around 95% of patients cured following chemotherapy. However, advancements in diagnosis and treatment are always needed to improve outcomes for patients with CC. Long non-coding (lnc) RNAs are non-coding transcripts that are longer than 200 nucleotides. LncRNAs can act as oncogenes or tumor suppressor genes. Deregulation of their expression has a key role in tumor development, angiogenesis, differentiation, migration, apoptosis, and proliferation. Furthermore, detection of cancer-associated lncRNAs in body fluids, such as blood, saliva, and urine of cancer patients, is emerging as a novel method for cancer diagnosis. Although there is evidence for the potential role of lncRNAs in a number of cancers of the female genital tract, their role in CC is poorly understood. This review summarizes the current knowledge of lncRNAs in gestational CC and how this may be applied to future therapeutic strategies in the treatment of this rare cancer., peer-reviewed more...
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- 2021
26. Nucleoside transporter-guided cytarabine-conjugated liposomes for intracellular methotrexate delivery and cooperative choriocarcinoma therapy
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Dongli Sun, Fengmei Wang, Caihong Zheng, Xiaodong Wu, Yunchun Zhao, Yao Yao, Chaoqun Li, Meng Zhang, Jiale Qin, and Weidong Fei
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Trophoblastic Tumor ,Pharmaceutical Science ,Medicine (miscellaneous) ,Apoptosis ,Nucleoside transporter ,Equilibrative nucleoside transporter 1 ,Applied Microbiology and Biotechnology ,Rats, Sprague-Dawley ,Drug Delivery Systems ,Tissue Distribution ,Choriocarcinoma ,Liposome ,Mice, Inbred BALB C ,biology ,Chemistry ,Cell Cycle ,Cytarabine ,Hep G2 Cells ,Endocytosis ,embryonic structures ,MCF-7 Cells ,Molecular Medicine ,Female ,Biotechnology ,medicine.drug ,Biomedical Engineering ,Mice, Nude ,Bioengineering ,Nucleoside Transport Proteins ,Cooperative therapy ,Cell Line, Tumor ,Medical technology ,medicine ,Animals ,Humans ,R855-855.5 ,Particle Size ,Research ,medicine.disease ,Drug Liberation ,Methotrexate ,Liposomes ,biology.protein ,Cancer research ,TP248.13-248.65 - Abstract
Gestational trophoblastic tumors seriously endanger child productive needs and the health of women in childbearing age. Nanodrug-based therapy mediated by transporters provides a novel strategy for the treatment of trophoblastic tumors. Focusing on the overexpression of human equilibrative nucleoside transporter 1 (ENT1) on the membrane of choriocarcinoma cells (JEG-3), cytarabine (Cy, a substrate of ENT1)-grafted liposomes (Cy-Lipo) were introduced for the targeted delivery of methotrexate (Cy-Lipo@MTX) for choriocarcinoma therapy in this study. ENT1 has a high affinity for Cy-Lipo and can mediate the endocytosis of the designed nanovehicles into JEG-3 cells. The ENT1 protein maintains its transportation function through circulation and regeneration during endocytosis. Therefore, Cy-Lipo-based formulations showed high tumor accumulation and retention in biodistribution studies. More importantly, the designed DSPE-PEG2k-Cy conjugation exhibited a synergistic therapeutic effect on choriocarcinoma. Finally, Cy-Lipo@MTX exerted an extremely powerful anti-choriocarcinoma effect with fewer side effects. This study suggests that the overexpressed ENT1 on choriocarcinoma cells holds great potential as a high-efficiency target for the rational design of active targeting nanotherapeutics. Graphic abstract more...
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- 2021
27. Chemical Induction of Trophoblast Hypoxia by Cobalt Chloride Leads to Increased Expression of DDIT3
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Alexander G. Tonevitsky, E N Knyazev, and S. Yu. Paul
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placenta ,Biophysics ,mTORC1 ,Biochemistry ,Pregnancy ,Placenta ,Cell Line, Tumor ,BeWo ,medicine ,choriocarcinoma ,Humans ,Inducer ,Caspase 7 ,Cell growth ,Chemistry ,Caspase 3 ,hypoxia ,Trophoblast ,General Chemistry ,General Medicine ,Cobalt ,unfolded protein response ,Hypoxia (medical) ,Cell Hypoxia ,Cell biology ,Trophoblasts ,medicine.anatomical_structure ,Gene Expression Regulation ,DDIT3 ,Apoptosis ,Biochemistry, Biophysics, and Molecular Biology ,embryonic structures ,Unfolded protein response ,hydroxyquinoline ,Female ,medicine.symptom ,Transcription Factor CHOP ,CHOP - Abstract
Abstract Choriocarcinoma cells BeWo b30 are used to model human placental trophoblast hypoxia using cobalt (II) chloride and hydroxyquinoline derivative (HD) as chemical inducers of hypoxia-inducible factor (HIF). In this study, it was shown that both substances activate the hypoxic pathway and the epithelial–mesenchymal transition and inhibit the pathways of cell proliferation. However, CoCl2 caused activation of the apoptosis pathway, increased the activity of effector caspases 3 and 7, and increased the expression of the unfolded protein response target DDIT3. The mTORC1 pathway was activated upon exposition to CoCl2, while HD suppressed this pathway, as it happens during real trophoblast hypoxia. Thus, effect of CoCl2 on BeWo cells can be a model of severe hypoxia with activation of apoptosis, while HD mimics moderate hypoxia. more...
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- 2021
28. Trophoblast uptake of DBP regulates intracellular actin and promotes matrix invasion
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Janesh K. Gupta, Annsha Joseph, Martin Hewison, Ankana Ganguly, Jennifer Tamblyn, Carl Jenkinson, Alexandra Shattock, Stephane R. Gross, and Dean Larner
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0301 basic medicine ,medicine.medical_specialty ,genetic structures ,Vitamin D-binding protein ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Calcitriol receptor ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Pre-Eclampsia ,Pregnancy ,Cell surface receptor ,Cell Line, Tumor ,Placenta ,Internal medicine ,medicine ,Humans ,Choriocarcinoma ,cardiovascular diseases ,Phosphorylation ,Vitamin D ,Extracellular Signal-Regulated MAP Kinases ,reproductive and urinary physiology ,Cell Nucleus ,Chemistry ,Vitamin D-Binding Protein ,Placentation ,Trophoblast ,Actins ,Trophoblasts ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Gene Knockdown Techniques ,Uterine Neoplasms ,embryonic structures ,Receptors, Calcitriol ,Female ,Intracellular ,circulatory and respiratory physiology - Abstract
Early pregnancy is characterised by elevated circulating levels of vitamin D binding protein (DBP). The impact of this on maternal and fetal health is unclear but DBP is present in the placenta, and DBP gene variants have been linked to malplacentation disorders such as preeclampsia. The functional role of DBP in the placenta was investigated using trophoblastic JEG3, BeWo and HTR8 cells. All three cell lines showed intracellular DBP with increased expression and nuclear localisation of DBP in cells treated with the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D). When cultured in the serum of mice lacking DBP (DBP−/−), JEG3 cells showed no intracellular DBP indicating uptake of exogenous DBP. Inhibition of the membrane receptor for DBP, megalin, also suppressed intracellular DBP. Elimination of intracellular DBP with DBP−/− serum or megalin inhibitor suppressed matrix invasion by trophoblast cells and was associated with increased nuclear accumulation of G-actin. Conversely, treatment with 1,25D enhanced matrix invasion. This was independent of the nuclear vitamin D receptor but was associated with enhanced ERK phosphorylation, and inhibition of ERK kinase suppressed trophoblast matrix invasion. When cultured with serum from pregnant women, trophoblast matrix invasion correlated with DBP concentration, and DBP was lower in first-trimester serum from women who later developed preeclampsia. These data show that the trophoblast matrix invasion involves uptake of serum DBP and associated intracellular actin-binding and homeostasis. DBP is a potential marker of placentation disorders such as preeclampsia and may also provide a therapeutic option for improved placenta and pregnancy health. more...
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- 2021
29. α-Solanine Inhibits Proliferation, Invasion, and Migration, and Induces Apoptosis in Human Choriocarcinoma JEG-3 Cells In Vitro and In Vivo
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Zhilong Chen, Qing Yang, Wei Yuan, Xingyao Xiong, Qiyi Zheng, Ting Gu, Anwen Yuan, Chen Li, and Yuting Wen
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α-Solanine ,Health, Toxicology and Mutagenesis ,proliferation ,lcsh:Medicine ,Mice, Nude ,Matrix metalloproteinase ,Toxicology ,migration ,Article ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Cell Movement ,Pregnancy ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Viability assay ,Choriocarcinoma ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Mice, Inbred BALB C ,Chemistry ,Cell growth ,lcsh:R ,apoptosis ,medicine.disease ,invasion ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,In vitro ,Tumor Burden ,Solanine ,Apoptosis ,030220 oncology & carcinogenesis ,embryonic structures ,Uterine Neoplasms ,choriocarcinoma cells ,Cancer research ,Female ,Signal Transduction - Abstract
α-Solanine, a bioactive compound mainly found in potato, exhibits anti-cancer activity towards multiple cancer cells. However, its effects on human choriocarcinoma have not been evaluated. In the present study, we investigated the effect of α-solanine on cell proliferation and apoptosis in human choriocarcinoma in vitro and in vivo. The results showed that α-solanine, at concentrations of 30 μM or below, did not affect the cell viability of the choriocarcinoma cell line JEG-3. However, colony formation was significantly decreased and cell apoptosis was increased in response to 30 μM α-solanine. In addition, α-solanine (30 μM) reduced the migration and invasion abilities of JEG-3 cells, which was associated with a downregulation of matrix metalloproteinases (MMP)-2/9. The in vivo findings provided further evidence of the inhibition of α-solanine on choriocarcinoma tumor growth. α-Solanine suppressed the xenograft tumor growth of JEG-3 cells, resulting in smaller tumor volumes and lower tumor weights. Apoptosis was promoted in xenograft tumors of α-solanine-treated mice. Moreover, α-solanine downregulated proliferative cellular nuclear antigen (PCNA) and Bcl-2 levels and promoted the expression of Bax. Collectively, α-solanine inhibits the growth, migration, and invasion of human JEG-3 choriocarcinoma cells, which may be associated with the induction of apoptosis. more...
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- 2021
30. The (pro)renin receptor and soluble (pro)renin receptor in choriocarcinoma
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Eugenie R. Lumbers, Celine Corbisier de Meaultsart, Saije K. Morosin, Richard G. S. Kahl, Sarah J. Delforce, and Kirsty G. Pringle
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Embryology ,Vacuolar Proton-Translocating ATPases ,Receptors, Cell Surface ,chemistry.chemical_compound ,Endocrinology ,Pregnancy ,Renin ,medicine ,Humans ,Secretion ,Choriocarcinoma ,Receptor ,Furin ,ATP6AP2 ,Syncytium ,Forskolin ,Cytotrophoblast ,biology ,Colforsin ,Obstetrics and Gynecology ,Cell Biology ,medicine.disease ,Molecular biology ,Trophoblasts ,medicine.anatomical_structure ,Reproductive Medicine ,chemistry ,embryonic structures ,Uterine Neoplasms ,biology.protein ,Female - Abstract
This study aimed to determine if the (pro)renin receptor (ATP6AP2) changes the cellular profile of choriocarcinomas from cytotrophoblast cells to terminally syncytialised cells and ascertain whether this impacts the invasive potential of choriocarcinoma cells. Additionally, we aimed to confirm that FURIN and/or site 1 protease (MBTPS1) cleave soluble ATP6AP2 (sATP6AP2) in BeWo choriocarcinoma cells and determine whether sATP6AP2 levels reflect the cellular profile of choriocarcinomas. BeWo choriocarcinoma cells were treated with ATP6AP2 siRNA, FURIN siRNA, DEC-RVKR-CMK (to inhibit FURIN activity), or PF 429242 (to inhibit MBTPS1 activity). Cells were also treated with forskolin, to induce syncytialisation, or vehicle and incubated for 48 h before collection of cells and supernatants. Syncytialisation was assessed by measuring hCG secretion (by ELISA) and E-cadherin protein levels (by immunoblot and immunocytochemistry). Cellular invasion was measured using the xCELLigence real-time cell analysis system and secreted sATP6AP2 levels measured by ELISA. Forskolin successfully induced syncytialisation and significantly increased both BeWo choriocarcinoma cell invasion (P < 0.0001) and sATP6AP2 levels (P = 0.02). Treatment with ATP6AP2 siRNA significantly inhibited syncytialisation (decreased hCG secretion (P = 0.005), the percent of nuclei in syncytia (P = 0.05)), forskolin-induced invasion (P = 0.046), and sATP6AP2 levels (P < 0.0001). FURIN siRNA and DEC-RVKR-CMK significantly decreased sATP6AP2 levels (both P < 0.0001). In conclusion, ATP6AP2 is important for syncytialisation of choriocarcinoma cells and thereby limits choriocarcinoma cell invasion. We postulate that sATP6AP2 could be used as a biomarker measuring the invasive potential of choriocarcinomas. Additionally, we confirmed that FURIN, not MBTPS1, cleaves sATP6AP2 in BeWo cells, but other proteases (inhibited by DEC-RVKR-CMK) may also be involved. more...
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- 2020
31. Disruption of p97/VCP induces autophagosome accumulation, cell cycle arrest and apoptosis in human choriocarcinoma cells
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Filiz Yavuz, Sevil Cayli, Cansu Sahin, and Raziye Desdicioğlu
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0301 basic medicine ,Autophagosome ,Cell cycle checkpoint ,Cell Survival ,Valosin-containing protein ,Autophagosome maturation ,Apoptosis ,Resting Phase, Cell Cycle ,03 medical and health sciences ,0302 clinical medicine ,Valosin Containing Protein ,Cell Line, Tumor ,Sequestosome-1 Protein ,Genetics ,medicine ,Autophagy ,Humans ,Choriocarcinoma ,RNA, Small Interfering ,Polyubiquitin ,Molecular Biology ,Cell Proliferation ,biology ,Chemistry ,Cell growth ,Autophagosomes ,G1 Phase ,Ubiquitination ,General Medicine ,Cell Cycle Checkpoints ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,Quinazolines ,Microtubule-Associated Proteins - Abstract
Gestational choriocarcinoma is aggressive trophoblastic disease. The development, progression and the cure of this disease is not well-established. p97/Valosin containing protein has been shown to play critical roles in many cellular processes. In various cancers, higher expression of p97/VCP has been reported and targeting of p97/VCP with its spesific inhibitors or siRNA's (siVCP) in cancer therapy was suggested. However, no study is avaible about the expression and function of p97/VCP in gestational choriocarcinoma. Hence, the aim of the study was to evaluate effects of p97/VCP inhibitor, DBeQ and siVCP on choriocarcinoma cells. We use human placental choriocarcinoma cell line (Jeg3) as model to find out the effects of DBeQ and VCP siRNA's (siVCP) on apoptotic and autophagic pathway by immunflouroscence staining, Western blotting, qPCR and flow-cytometry. p97/VCP siRNA's and DBeQ induced accumulation of autophagic proteins, LC3II and p62 in the cytoplasm of Jeg3 cells detected. Concurrently, Jeg3 cells treated with DBeQ and siVCP demonstrated G0/G1 cell cycle arrest, accompanied by accumulation of poly-ubiquitinated proteins. Moreover, disruption of p97/VCP by siRNA and DBeQ inhibited cancer cell growth managing the caspases-3 and -7. Our results show that inhibition of p97/VCP activity with DBeQ and depletion of p97/VCP expression with siRNA in Jeg3 cells induce caspase activation, inhibits cell proliferation and leads to a defect in autophagosome maturation, thus providing potential target for the prevention and treatment of choriocarcinoma. more...
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- 2020
32. Targeted-regulating of miR-515-5p by LncRNA LOXL1-AS1 on the proliferation and migration of trophoblast cells
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Li Zhang, Qingfeng Wan, and Huiyun Zhou
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0301 basic medicine ,Small interfering RNA ,Clinical Biochemistry ,Apoptosis ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Pregnancy ,microRNA ,medicine ,Biomarkers, Tumor ,Humans ,MTT assay ,RNA, Antisense ,Choriocarcinoma ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,Chemistry ,Trophoblast ,Cell migration ,Transfection ,eye diseases ,Cell biology ,Trophoblasts ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,embryonic structures ,Uterine Neoplasms ,Female ,RNA, Long Noncoding ,Amino Acid Oxidoreductases ,Signal transduction - Abstract
Objective This study aims to elucidate the molecular mechanism of LOXL1-AS1 in proliferation and migration of trophoblast cells. Methods We have used specific small interfering RNAs (si-RNA) and microRNA (mi-RNA) to knock down the target gene or m-RNA. In this regard we used following siRNAs: si-NC, si-LOXL1-AS1, pcDNA-NC, pcDNA-LOXL1-AS1, miR-NC, miR-515-5p. These si-RNA and miRNA were transfected into JeG-3 cells. Real-time quantitative PCR (RT-qPCR) was used to detect the expressions of LOXL1-AS1 and miR-515-5p. Western blot was used to detect Cyclin D1, matrix metalloproteinase 2 (MMP2), matrix metalloproteinases 9 (MMP9), phosphorylated p65 (p-p65), profilin of phosphorylated nuclear transcription factor κB (p-IκBα). MTT assay was used to detect cell survival rate, and the luciferase assay was used to detected the targeting relationship of LOXL1-AS1 and miR-515-5p. Results Our results showed that human placental trophoblast cells had higher level of LOXL1-AS1 in comparison to human choriocarcinoma cells, however, human placental trophoblast cells had lower level of miR-515-5p. In addition, the expression of CyclinD1, MMP2, MMP9 were significantly decreased in JeG-3 cell lines. We observed lower cell survival rate and lower cell migration number in JeG-3 cell lines. Our results demonstrated that LOXL1-AS1 could target miR-515-5p, and subsequently reverse the inhibitory effect of LOXL1-AS1 on proliferation and migration in JEG-3 cells. Also, lower expressions of p-p65 and p-IкBα in JeG-3 cells showed that miR-515-5p could reversed the inhibitory effect of LOXL1-AS1 on NF-κB signaling pathway. Conclusions The low expression of LOXL1-AS1 inhibits the proliferation and migration of human choriocarcinoma cells, which might be related to miR-515-5p and NF-κB signaling pathways. more...
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- 2020
33. Core 2 β1,6-N-acetylglucosaminyltransferases accelerate the escape of choriocarcinoma from natural killer cell immunity
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Eiko Yamamoto, Kenichi Nakamura, Hiroaki Kajiyama, Kaoru Niimi, Shiro Suzuki, Fumitaka Kikkawa, Yoshiki Ikeda, and Kimihiro Nishino
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0301 basic medicine ,GTD, gestational trophoblastic disease ,QH301-705.5 ,Cell ,Biophysics ,Natural killer cell ,QD415-436 ,Biochemistry ,LEL, Lycopersicon esculentum lectin ,Human chorionic gonadotropin ,GTN, gestational trophoblastic neoplasm ,03 medical and health sciences ,0302 clinical medicine ,EVT, extravillous trophoblast ,PSTT, placental site trophoblastic tumor ,MHC class I ,medicine ,MUC1, mucin1 ,Choriocarcinoma ,Biology (General) ,TRAIL, tumor necrosis factor-related apoptosis inducing ligand ,C2GnT, core2 beta 1, 6-N acetylglucosaminyl transferase ,MUC1 ,reproductive and urinary physiology ,biology ,C2GnT ,Chemistry ,HLA, human leukocyte antigen ,MICA, MHC class I-related chain A ,medicine.disease ,NKG2D, natural killer group 2 member D ,O-glycan ,H-hCG, hyperglycosylated human chorionic gonadotropin ,030104 developmental biology ,medicine.anatomical_structure ,Apoptosis ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer research ,biology.protein ,Tumor necrosis factor alpha ,hCG, human chorionic gonadotropin ,DR4, death receptor 4 ,Immunosuppression ,Research Article - Abstract
Hyperglycosylated human chorionic gonadotropin (H-hCG) is secreted from choriocarcinoma and contains a core2 O-glycan formed by core2 β1,6-N-acetylglucosaminyl transferase (C2GnT). Choriocarcinoma is considered immunogenic as it is gestational and contains paternal chromosomal components. Here we examined the function of C2GnT in the evasion of choriocarcinoma cells from natural killer (NK) cell-mediating killing. We determined that C2GnT is highly expressed in malignant gestational trophoblastic neoplasms. C2GnT KO downregulates core2 O-glycan expression in choriocarcinoma cells, which are more efficiently killed by NK cells than control cells. C2GnT KO cell containing tumor necrosis factor-related apoptosis inducing ligand have lower viability than control cells. Additionally, poly-N-acetyllactosamine in core2 branched oligosaccharides on MHC class I-related chain A (MICA) and mucin1 (MUC1) is significantly reduced in C2GnT KO cells. Meanwhile, the cumulative survival rate of nude mice inoculated with C2GnT KO tumors was higher than that of the control group. These findings suggest that choriocarcinoma cells may escape NK cell-mediated killing via glycosylation of MICA and MUC1., Graphical abstract Image 1, Highlights • C2GnT knockout reduces core2 O-glycan expression in choriocarcinoma cells • C2GnT KO cells are more readily killed by NK cells • C2GnT KO cells containing TRAIL have lower viability than controls • MHC class I-related chain A and MUC1 glycosylation is reduced in C2GnT KO cells • Survival rate of nude mice inoculated with C2GnT KO tumors is higher than controls more...
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- 2020
34. The comparison of pegylated liposomal doxorubicin and beta-carotene effects on JAR and JEG-3 choriocarcinoma human cell culture models
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Seyit Ahmet Erol, Muge Harma, Mehmet Ibrahim Harma, Görker Sel, and Ishak Ozel Tekin
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0301 basic medicine ,Vitamin ,Combination therapy ,medicine.drug_class ,lcsh:Medicine ,Pharmacology ,JEG-3 cell culture ,lcsh:Gynecology and obstetrics ,Flow cytometry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Annexin ,Pegylated liposomal doxorubicin ,medicine ,choriocarcinoma ,JAR cell culture ,lcsh:RG1-991 ,Original Investigation ,medicine.diagnostic_test ,business.industry ,lcsh:R ,Choriocarcinoma ,Obstetrics and Gynecology ,medicine.disease ,030104 developmental biology ,beta-carotene ,chemistry ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,embryonic structures ,lipids (amino acids, peptides, and proteins) ,Gonadotropin ,business - Abstract
Objective: The aim was to investigate the effectiveness of pegylated liposomal doxorubicin (PLD), beta-carotene, and a combination of PLD and beta-carotene on JAR and JEG-3 human choriocarcinoma (CC) cell lines for the treatment of CC. Material and Methods: JAR and JEG-3 cells were cultured. PLD and beta-carotene trial groups were determined with different doses (for single drug trial; PLD 1, 2, 5 μg/mL and beta-carotene 1, 5, 10 μg/mL, and for combined drug trial; all PLD doses combined with beta-carotene 5 μg/mL). Drugs were administered to cultures simultaneously, and 72 hours later the cells were detached using trypsin-ethylenediamine tetraacetic acid solution. The percentage of apoptotic cells was determined by flow cytometry after annexin V staining. One set of the supernatant was collected before trypsin application to investigate beta-human chorionic gonadotropin (β-hCG) and hyperglycosylated hCG (H-hCG) levels. Statistical analyses of the apoptotic ratios were performed using Shapiro-Wilk, Kruskal-Wallis and Mann-Whitney U tests. Results: Apoptosis increased in JAR and JEG-3 cultures after treatment with all doses of PLD (p more...
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- 2020
35. Targeting EpCAM by a Bispecific Trifunctional Antibody Exerts Profound Cytotoxic Efficacy in Germ Cell Tumor Cell Lines
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Anna Casati, Gabriele Calaminus, Daniel Nettersheim, Dagmar Dilloo, Mahsa Mohseni, Rogerio B. Craveiro, Hubert Schorle, Stefan Schönberger, and Daniela Kraft
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0301 basic medicine ,embryonal carcinoma ,Cancer Research ,T cell ,medicine.medical_treatment ,Catumaxomab ,Medizin ,lcsh:RC254-282 ,Article ,Embryonal carcinoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,choriocarcinoma ,Cytotoxic T cell ,germ cell tumors ,biology ,seminoma ,Epithelial cell adhesion molecule ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Trifunctional antibody ,CD3 ,bispecific antibody ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,EpCAM ,biology.protein ,Cancer research ,immunotherapy ,Antibody ,medicine.drug - Abstract
Outcome in high-risk patients with refractory or relapsed germ cell tumours (GCT) remains poor. Novel strategies enhancing therapeutic efficacy whilst limiting therapeutic burden are warranted, yet immunotherapy approaches geared towards activating endogenous antitumor responses have not been successful thus far. Redirection of cytotoxic effector cells by bispecific antibodies represents a promising approach in this setting. We demonstrate that the Epithelial Cell Adhesion Molecule (EpCAM) is broadly expressed in GCT cell lines of different histologic origin including seminoma, choriocarcinoma (CHC), and embryonal carcinoma (EC). In these GCT lines of variable EpCAM surface expression, targeting T cells by the prototypic bispecific EpCAM/CD3-antibody (bAb) Catumaxomab together with natural killer (NK) cell engagement via the Fc domain promotes profound cytotoxicity across a broad range of antibody dilutions. In contrast, tumor cell lysis mediated by either immune cell subset alone is influenced by surface density of the target antigen. In the CHC line JAR, NK cell-dependent cytotoxicity dominates, which may be attributed to differential surface expression of immunomodulatory proteins such as MHC-I, CD24, and Fas receptors on CHC and EC. In view of redirecting T cell therapy mediated by bispecific antibodies, such differences in GCT immunophenotype potentially favoring immune escape are worth further investigation. more...
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- 2020
36. SAT-LB89 Choriocarcinoma Induced Hyperthyroidism: Molecular Mimicry Between HCG and TSH
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Anvitha Reddy Ankireddypalli, Sridhar Srinivasan Nambi, Chandriya Chandran, Rabindra Lamichhane, and Boradia Chirag
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Thyroid ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Choriocarcinoma ,medicine.disease_cause ,medicine.disease ,Thyroid Disorders Case Reports II ,Molecular mimicry ,Endocrinology ,Internal medicine ,medicine ,hormones, hormone substitutes, and hormone antagonists ,AcademicSubjects/MED00250 - Abstract
Introduction: Human chorionic gonadotropin(HCG) induced hyperthyroidism is a rare cause of hyperthyroidism. It is usually seen in conditions with extremely high beta HCG levels like hyperemesis gravidarum, hydatiform moles and germ cell tumors. We present a young male patient who had primary mediastinal choriocarcinoma with widespread lung metastasis and hyperthyroidism. Case: 18-year-old male presented to the emergency department for a fever of 105 F, cough, shortness of breath and night sweats for 9 days. He also reported unintentional weight loss for the past few weeks. Upon presentation, he was tachycardic at 104 beats/min, tachypneic and febrile. Physical examination revealed bibasilar crackles. Thyroid and scrotal examination were unremarkable. Laboratory work was significant for leukocytosis of 18.7 k/cmm, AST: 69 Unit/L, ALT: 60 Unit/L, ALP: 123 unit/L and LDH: 438Unit/L. Chest radiology showed bilateral multiple cannonball lesions with mediastinal and periaortic lymphadenopathy. CT chest, abdomen, and pelvis revealed innumerable diffuse bilateral lung masses, large anterior mediastinal mass, enlarged periaortic and paratracheal lymph nodes. Infectious workup was unremarkable. MRI brain revealed leptomeningeal involvement and vasogenic edema. Ultrasound of testicles revealed bilateral severe microlithiasis. CT guided biopsy of lung mass showed poorly differentiated choriocarcinoma. Treatment was initiated with systemic steroids, bleomycin, and cisplatin. Additional blood work revealed, B-HCG:736,598 mIU/mL, TSH:0.009UIU/ml, free T4:2.95ng/dL and total T3: 292.3ng/Dl. Thyroid radioiodine uptake scan was normal and planar imaging was also normal. Treatment with methimazole was deferred due to the up-trending transaminases and the resolution of tachycardia. Repeat labs after chemotherapy were TSH: 0.005UIU/mL, free T4: 2.04ng/dL, free T3:1.70pg/mL and BHCG: 202,471UIU/mL. Unfortunately, the patient had chemotherapy-resistant choriocarcinoma and succumbed to death after 4 cycles. Discussion: Beta HCG has an intrinsic thyroid-stimulating activity. The HCG -alpha subunit is common to all glycoprotein hormones like follicle-stimulating hormone, luteinizing hormone or thyroid-stimulating hormone. Frankly elevated levels should be treated symptomatically with beta-blockers and/or anti-thyroid drugs. Subclinical hyperthyroidism should be monitored closely. Some patients do not develop hyperthyroidism or a toxic goiter, as it is dependent on the timing of onset of cancer or due to the secondary modifications of HCG that can affect the bioactivity of HCG on the TSH receptor. This case draws our attention to the importance of focusing on the molecular mimicry of the HCG and TSH and management of HCG mediated hyperthyroidism. more...
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- 2020
37. Metabolic Reprogramming of Trophoblast Cells in Response to Hypoxia
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I M Tsypina, E N Knyazev, Gennady T. Sukhikh, Galina S. Zakharova, L. A. Astakhova, and Alexander G. Tonevitsky
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0301 basic medicine ,Nitric Oxide Synthase Type III ,Cell ,Protein Serine-Threonine Kinases ,Mitochondrion ,Models, Biological ,Oxidative Phosphorylation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Pre-Eclampsia ,Pregnancy ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Placenta ,medicine ,Humans ,Chemistry ,Gene Expression Profiling ,Choriocarcinoma ,Membrane Proteins ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,RNA-Binding Proteins ,Trophoblast ,General Medicine ,Hypoxia (medical) ,Cellular Reprogramming ,Oxyquinoline ,medicine.disease ,Cell Hypoxia ,Trophoblasts ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,embryonic structures ,Female ,medicine.symptom ,Carrier Proteins ,Glycolysis ,Reprogramming ,030217 neurology & neurosurgery - Abstract
Hypoxia of trophoblast cells is an important regulator of normal development of the placenta. However, some pathological states associated with hypoxia, e.g. preeclampsia, impair the functions of placental cells. Oxyquinoline derivative inhibits HIF-prolyl hydroxylase by stabilizing HIF-1 transcription complex, thus modeling cell response to hypoxia. In human choriocarcinoma cells BeWo b30 (trophoblast model), oxyquinoline increased the expression of a core hypoxia response genes along with up-regulation of NOS3, PDK1, and BNIP3 genes and down-regulation of the PPARGC1B gene. These changes in the expression profile attest to activation of the metabolic cell reprogramming mechanisms aimed at reducing oxygen consumption by enabling the switch from aerobic to anaerobic glucose metabolism and the respective decrease in number of mitochondria. The possibility of practical use of the therapeutic properties of oxyquinoline derivatives is discussed. more...
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- 2019
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38. Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-κB Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma
- Author
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Sanjun Shi, Lili Wei, Lee Yong Lim, Xianjue Chen, Kun Shi, Bing Yang, Chenyuan Wang, Leah R. Benington, and Jingxin Mo
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0301 basic medicine ,Proton Magnetic Resonance Spectroscopy ,Medicine (miscellaneous) ,Apoptosis ,Ascorbic Acid ,Polyethylene Glycols ,0302 clinical medicine ,Cell Movement ,Tissue Distribution ,Choriocarcinoma ,Neoplasm Metastasis ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Micelles ,Mice, Inbred BALB C ,Chemistry ,NF-kappa B ,Hydrogen-Ion Concentration ,Glutathione ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Drug carrier ,Oxidation-Reduction ,Signal Transduction ,Research Paper ,medicine.drug ,Ascorbyl phosphate palmitate derivative ,Mice, Nude ,Succinimides ,Antineoplastic Agents ,03 medical and health sciences ,Cell Line, Tumor ,Orthotopic choriocarcinoma ,Lysosome ,Dual-responsive micelles ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,NF-κB signaling pathway ,Ascorbic acid ,medicine.disease ,Disease Models, Animal ,Drug Liberation ,IκBα ,Methotrexate ,030104 developmental biology ,Cancer cell ,Cancer research ,Reactive Oxygen Species - Abstract
Gestational trophoblastic neoplasia (GTN), the most aggressive form of which is choriocarcinoma, can result from over-proliferation of trophoblasts. Treating choriocarcinoma requires high doses of systemic chemotherapeutic agents, which result in nonspecific drug distribution and severe toxicity. To overcome these disadvantages and enhance chemotherapeutic efficacy, we synthesized redox- and pH-sensitive, self-assembling, ascorbic acid-derived (PEG-ss-aAPP) micelles to deliver the drug methotrexate (MTX). Methods: We developed and tested self-assembling PEG-ss-aAPP micelles, which release their drug cargo in response to an intracellular reducing environment and the acidity of the early lysosome or tumoral microenvironment. Uptake into JEG3 choriocarcinoma cancer cells was examined using confocal microscopy and transmission electron microscopy. We examined the ability of MTX-loaded PEG-ss-aAPP micelles to inhibit metastasis in an orthotopic mouse model of human choriocarcinoma. Results: Drug-loaded micelles had encapsulation efficiency above 95%. Particles were spherical based on transmission electron microscopy, with diameters of approximately 229.0 nm based on dynamic light scattering. The drug carrier responded sensitively to redox and pH changes, releasing its cargo in specific environments. PEG-ss-aAPP/MTX micelles efficiently escaped from lysosome/endosomes, and they were effective at producing reactive oxygen species, strongly inducing apoptosis and inhibiting invasion and migration. These effects correlated with the ability of PEG-ss-aAPP/MTX micelles to protect IκBα from degradation, which in turn inhibited translocation of NF-κB p65 to the nucleus. In an orthotopic mouse model of human choriocarcinoma, PEG-ss-aAPP/MTX micelles strongly inhibited primary tumor growth and significantly suppressed metastasis without obvious side effects. Conclusions: Our results highlight the potential of PEG-ss-aAPP micelles for targeted delivery of chemotherapeutic agents against choriocarcinoma. more...
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- 2019
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39. Apomorphine induces mitochondrial-dysfunction-dependent apoptosis in choriocarcinoma
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Jiyeon Ham, Jin Young Lee, Whasun Lim, and Gwonhwa Song
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0301 basic medicine ,Embryology ,Apomorphine ,Antineoplastic Agents ,Apoptosis ,Pharmacology ,Mitochondrion ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Pregnancy ,medicine ,Humans ,Choriocarcinoma ,reproductive and urinary physiology ,Caspase ,Cell Proliferation ,Membrane Potential, Mitochondrial ,030219 obstetrics & reproductive medicine ,biology ,Endoplasmic reticulum ,Intrinsic apoptosis ,Obstetrics and Gynecology ,Cell Biology ,medicine.disease ,Endoplasmic Reticulum Stress ,female genital diseases and pregnancy complications ,Mitochondria ,030104 developmental biology ,Reproductive Medicine ,Paclitaxel ,chemistry ,embryonic structures ,Dopamine Agonists ,Uterine Neoplasms ,biology.protein ,Female ,Reactive Oxygen Species ,medicine.drug ,Signal Transduction - Abstract
Apomorphine is a derivative of morphine that is used for the treatment of Parkinson’s disease because of its effects on the hypothalamus. Therapeutic effects of apomorphine have also been reported for various neurological diseases and cancers. However, the molecular mechanisms of the antitumor effects of apomorphine are not clear, especially with respect to choriocarcinoma. This is the first study to elucidate the anticancer effects of apomorphine on choriocarcinoma. We found that apomorphine suppressed the viability, proliferation, ATP production, and spheroid formation of JEG3 and JAR choriocarcinoma cells. Moreover, apomorphine activated the intrinsic apoptosis pathway by activating caspases and inhibited the production of anti-apoptotic proteins in choriocarcinoma cells. Further, apomorphine caused depolarization of mitochondria, calcium overload, energy deprivation, and endoplasmic reticulum stress in JEG3 and JAR cells. We confirmed synergistic effects of apomorphine with paclitaxel, a traditional chemotherapeutic agent, and propose that apomorphine could be a potential therapeutic agent in choriocarcinoma and an important candidate for drug repositioning that could help overcome resistance to conventional chemotherapy. more...
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- 2020
40. Inhibitory effect of dihydromyricetin on the proliferation of JAR cells and its mechanism of action
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Yanjie Lu, Xiaoru Li, Xiujun Liang, Yuhong Li, Qian Xu, Yanzhen Zuo, and Dayong Sun
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0301 basic medicine ,dihydromyricetin ,Cancer Research ,Cell cycle checkpoint ,proliferation ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Cyclin D1 ,choriocarcinoma ,medicine ,MTT assay ,medicine.diagnostic_test ,Chemistry ,Cell growth ,JAR cells ,Articles ,Cell cycle ,Molecular biology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,Cancer cell ,cell cycle ,Cyclin A1 - Abstract
Dihydromyricetin (DMY) is a novel natural drug with antitumor activity against some cancer cells without obvious toxicity. Previously, its apoptotic effect on human choriocarcinoma was detected. The present study further investigated the therapeutic potential of DMY as a new drug for the treatment of choriocarcinoma, as well as its anti-proliferative effect and mechanism of action. The short-term proliferation of JAR cells was determined by MTT assay, whereas the effect of DMY on long-term cell proliferation was determined by colony forming assay. Flow cytometry was used to detect changes in the cell cycle. Furthermore, western blotting was used to detect the expression levels of proliferation-associated proteins such as cyclin A1, cyclin D1, SMAD3 and SMAD4. Reverse transcription-quantitative PCR (RT-qPCR) was used to quantify mRNA expression levels. The results indicated that DMY inhibited short and long-term proliferation of JAR cells in a concentration-dependent manner. Flow cytometry demonstrated S/G2/M cell cycle arrest, and western blotting revealed the downregulation of SMAD3, SMAD4, cyclin A1 and cyclin D1 expression levels. The results of RT-qPCR and western blotting were consistent. Overall, the findings of the present study suggest that DMY inhibits the proliferation of human choriocarcinoma JAR cells, potentially through cell cycle arrest via the downregulation of cyclin A1, cyclin D1, SMAD3 and SMAD4 expression levels. more...
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- 2020
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41. Bavachin suppresses human placental choriocarcinoma cells by targeting electron transport chain complexes and mitochondrial dysfunction
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Jin Young Lee, Gwonhwa Song, and Whasun Lim
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0301 basic medicine ,Placenta ,Inflammation ,Oxidative phosphorylation ,Mitochondrion ,Biochemistry ,Electron Transport ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Physiology (medical) ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Caspase ,Flavonoids ,biology ,Chemistry ,Endoplasmic reticulum ,Cancer ,medicine.disease ,female genital diseases and pregnancy complications ,Mitochondria ,030104 developmental biology ,Apoptosis ,Cell culture ,embryonic structures ,biology.protein ,Cancer research ,Female ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - Abstract
Phytoestrogens are naturally derived estrogen-like therapeutic compounds that have long been studied for their role as anti-cancer agents and supplements during chemotherapy. Bavachin is a therapeutic phytoestrogen used to treat cancer, inflammation, and diabetes mellitus. Though the therapeutic effects of bavachin on various diseases have been explored, its anti-cancer effects and related mechanisms in human placental choriocarcinoma remain unknown. This is the first study to identify the anti-cancer potential of bavachin on human placental choriocarcinoma cell lines JEG3 and JAR. Placental mitochondria support the elevated energy production required for placental development, through oxidative phosphorylation (OXPHOS). Based on this concept, we hypothesized that mitochondrial targeting by bavachin may contribute to anti-cancer activities in high-OXPHOS subtypes of cancer such as placental choriocarcinoma. Apoptosis and caspase activities were increased by bavachin in placental choriocarcinoma cells. Bavachin altered metabolic phenotypes by regulating electron transport chain complex and OXPHOS to suppress choriocarcinoma cell proliferation. It also led to calcium disruption and endoplasmic reticulum stress accompanied by mitochondrial membrane potential depolarization. It showed synergistic anti-cancer effects with paclitaxel on placental choriocarcinoma cells. Taken together, we suggest that bavachin has therapeutic potential against placental choriocarcinoma and may be used to counter paclitaxel-induced toxicity. more...
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- 2020
42. The Effects of 5,6,7,8,3′,4′-Hexamethoxyflavone on Apoptosis of Cultured Human Choriocarcinoma Trophoblast Cells
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Mengling Zhang, Zhen Wang, Jian Liu, Juan Liu, Rui Zhang, Hongliang Wang, Yang Shan, and Huanling Yu
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safety ,Cell ,Pharmaceutical Science ,Cell morphology ,Nobiletin ,Article ,Analytical Chemistry ,Flow cytometry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Organic chemistry ,Cell Line, Tumor ,Drug Discovery ,medicine ,BeWo cells ,Humans ,Viability assay ,Choriocarcinoma ,Physical and Theoretical Chemistry ,030304 developmental biology ,0303 health sciences ,nobiletin ,medicine.diagnostic_test ,Chemistry ,Organic Chemistry ,apoptosis ,Cell cycle ,Flavones ,Molecular biology ,trophoblast ,Neoplasm Proteins ,Trophoblasts ,medicine.anatomical_structure ,Chemistry (miscellaneous) ,Apoptosis ,Cell culture ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Molecular Medicine ,Female ,Apoptosis Regulatory Proteins - Abstract
5,6,7,8,3,4&prime, Hexamethoxyflavone, also called nobiletin (NOB), widely found in the citrus peel, is one of the main byproducts in citrus processing. NOB is considered safe, but its safety for women during pregnancy is unknown. Therefore, the effect of NOB on apoptosis in human choriocarcinoma trophoblast cells (BeWo cells) was evaluated. Cells were divided into four groups and cultured with different concentrations of NOB (0, 10, 33, and 100 &mu, M) for 12, 24, 36, and 48 h respectively. Cell viability was detected by CCK-8 assay, cell morphology was detected by a Cell Imaging Multi-Mode Reader, and cell cycle and apoptosis were detected by flow cytometry. Cleaved PARP level, the expressions of B cell lymphoma 2 (BCL2) family proteins, and p53 pathway proteins were detected by Western blot. The results showed that after 48 h of cell culture, the cell viability was decreased significantly, but apoptosis was significantly increased. Compared to the cells without NOB treatment, the cells treated with NOB at 10 or 33 &mu, &Mu, showed no significant differences in the number of suspended cells or late apoptosis rate, except the increase of cell viability. Treatment of NOB at the concentration of 100 &mu, M improved cell viability, attenuated apoptosis, decreased suspended cells, and did not alter the G1 phase arrest, compared with the non-NOB-treated group after 48 h of culturing. The 100 &mu, NOB treatment increased the levels of BCL2 and BCLXL, and decreased p53 accumulation in BeWo cells at 48 h, but had no effect on the expression of BAX, BAK, BAD, p21, and G1 phase arrest. These findings provide evidence that NOB (10, 33, and 100 &mu, ) was safe for BeWo cells. NOB at the concentration of 100 &mu, could attenuate apoptosis in BeWo cells, which might be helpful to prevent pregnancy-related diseases caused by apoptosis. more...
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- 2020
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43. Production of an anti-angiogenic factor sFLT1 is suppressed via promoter hypermethylation of FLT1 gene in choriocarcinoma cells
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Takeshi Nagamatsu, Tetsushi Tsuruga, Tadashi Sasagawa, Masabumi Shibuya, Kazuki Morita, Tomoyuki Fujii, Mayuyo Mori-Uchino, and Atsushi Jinno-Oue
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0301 basic medicine ,Vascular Endothelial Growth Factor A ,Cancer Research ,Angiogenesis ,Bisulfite sequencing ,sFLT1 ,Mice ,0302 clinical medicine ,Protein Isoforms ,Choriocarcinoma ,Tumor suppressor gene ,Hypoxia ,Promoter Regions, Genetic ,reproductive and urinary physiology ,DNA methylation ,Neovascularization, Pathologic ,Chemistry ,Trophoblast ,Methylation ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,female genital diseases and pregnancy complications ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,Female ,Research Article ,RNA Splicing ,lcsh:RC254-282 ,03 medical and health sciences ,Cell Line, Tumor ,Genetics ,medicine ,Gene silencing ,Animals ,Humans ,RNA, Messenger ,Vascular Endothelial Growth Factor Receptor-1 ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,CpG Islands - Abstract
Background Soluble Fms-like tyrosine kinase-1 (sFLT1) as an anti-angiogenic factor is abundantly expressed in placental trophoblasts. Choriocarcinoma, a malignant tumor derived from trophoblasts, is known to be highly angiogenic and metastatic. However, the molecular mechanism underlying angiogenesis in choriocarcinoma pathogenesis remains unclear. We aimed to investigate the mRNA expression and DNA methylation status of the FLT1 gene in human choriocarcinoma cells and trophoblast cells. Methods qRT-PCR, Western blotting and ELISA were conducted to evaluate the mRNA and protein expression levels of sFLT1. 5-aza-2′-deoxycytidine (5azadC) treatment and bisulfite sequencing were used to study the FLT1 gene promoter methylation. The effect of sFLT1 on choriocarcinoma growth and angiogenesis was evaluated in a xenograft mouse model. Results Expression of the FLT1 gene was strongly suppressed in choriocarcinoma cell lines compared with that in the primary trophoblasts. Treatment of choriocarcinoma cell lines with 5azadC, a DNA methyltransferase inhibitor, markedly increased in mRNA expression of three FLT1 splice variants and secretion of sFLT1 proteins. Bisulfite sequencing revealed that the CpG hypermethylation was observed at the FLT1 promoter region in choriocarcinoma cell lines and a human primary choriocarcinoma tissue but not in human trophoblast cells. Interestingly, in 5azadC-treated choriocarcinoma cell lines, sFLT1 mRNA expression and sFLT1 production were further elevated by hypoxic stimulation. Finally, as expected, sFLT1-expressing choriocarcinoma cells implanted into nude mice showed significantly slower tumor growth and reduced microvessel formation compared with GFP-expressing control choriocarcinoma cells. Conclusions Inhibition of sFLT1 production by FLT1 silencing occurs via the hypermethylation of its promoter in choriocarcinoma cells. The stable expression of sFLT1 in choriocarcinoma cells resulted in the suppression of tumor growth and tumor vascularization in vivo. We suggest that the FLT1 gene may be a cell-type-specific tumor suppressor in choriocarcinoma cells. more...
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- 2020
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44. Valproic acid transport in the choriocarcinoma placenta cell line JEG-3 proceeds independently of the proton-dependent transporters MCT1 and MCT4
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Masaki Kobayashi, Takeshi Hirano, Ken Iseki, Ayako Nishimura, Yuri Ishiguro, Katsuya Narumi, and Ayako Furugen
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Monocarboxylic Acid Transporters ,0301 basic medicine ,Small interfering RNA ,Muscle Proteins ,Pharmaceutical Science ,Pharmacology ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Placenta ,medicine ,Humans ,Pharmacology (medical) ,RNA, Small Interfering ,Monocarboxylate transporter ,Valproic Acid ,Gene knockdown ,Symporters ,biology ,Chemistry ,Choriocarcinoma ,Biological Transport ,Transporter ,Hydrogen-Ion Concentration ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,embryonic structures ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Protons ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Medication therapy is the first line of treatment in the management of epilepsy. Fetal exposure to valproic acid (VPA), an antiepileptic drug, poses an elevated risk of teratogenicity in early pregnancy. Some studies have reported that monocarboxylate transporters (MCTs) may be involved in the placental transport of VPA. However, it has not been determined which MCTs contribute to VPA transport into the placenta. Therefore, the aim of this study was to determine how MCTs contribute to VPA transport into the placenta using the human placenta choriocarcinoma cell line JEG-3. VPA uptake was investigated using JEG-3 cells and radiolabeled VPA. MCT expression in JEG-3 cells was detected using RT-PCR and western blotting. Knockdown of MCTs was carried out using siRNAs. VPA uptake into JEG-3 cells was pH- and concentration-dependent, and described by using the Michaelis–Menten equation (Km = 0.95 ± 0.17 mM; Vmax = 19.3 ± 1.21 nmol/mg protein/15 s). MCT1 and MCT4 expression was found in JEG-3 cells, and typical MCT inhibitors significantly inhibited VPA uptake into JEG-3 cells. However, knockdown of MCT1 and MCT4 did not alter VPA uptake. In conclusion, VPA transport is mediated by a proton-dependent transporter in JEG-3 cells, but not by MCT1 and MCT4. more...
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- 2018
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45. Naringenin suppresses growth of human placental choriocarcinoma via reactive oxygen species-mediated P38 and JNK MAPK pathways
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Sunwoo Park, Gwonhwa Song, Whasun Lim, and Fuller W. Bazer
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0301 basic medicine ,MAPK/ERK pathway ,Naringenin ,MAP Kinase Kinase 4 ,MAP Kinase Signaling System ,Pharmaceutical Science ,Apoptosis ,Mitochondrion ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Movement ,Pregnancy ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,Choriocarcinoma ,Phosphorylation ,Protein kinase B ,reproductive and urinary physiology ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,food and beverages ,medicine.disease ,Antineoplastic Agents, Phytogenic ,female genital diseases and pregnancy complications ,Mitochondria ,Cell biology ,030104 developmental biology ,Complementary and alternative medicine ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Flavanones ,embryonic structures ,Molecular Medicine ,Female ,Mitogen-Activated Protein Kinases ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt - Abstract
Background Human placental choriocarcinoma is a gestational trophoblastic tumor with high rates of metastasis and reoccurrence. However, some patients with choriocarcinoma are chemoresistance to conventional chemotherapeutic agents. Hypothesis Naringenin increases apoptosis in human placental choriocarcinoma cells. Methods We investigated the effects of naringenin on proliferation and migration of JAR and JEG3 cells, and performed TUNEL and Annexin V/PI staining assays to examine apoptotic effects of naringenin on both cells. In addition, we studied the loss of mitochondrial membrane potential (MMP) and the production of mitochondrial reactive oxygen species (ROS) to determine the specific reason for apoptosis of choriocarcinoma cells being mediated via mitochondria. Consistent with the induction of production of ROS by naringenin in both choriocarcinoma cell lines, we investigated lipid peroxidation and glutathione levels in both JAR and JEG3 cells since both are affected by ROS. We next determined dose-dependent effects of naringenin and its pharmacological inhibitors on signal transduction pathways in JAR and JEG3 cells by western blot analyses. Results Naringenin reduced viability and migratory functions of both cell lines, and increased mitochondria related apoptosis induced by ROS and lipid peroxidation, decreased glutathione and decreased mitochondrial membrane potential MMP in a dose-dependent manner. We also determined naringenin activated phosphorylation of ERK1/2, P38, JNK and P70S6K in JAR and JEG3 cells in a dose-response manner. Although naringenin induced phosphorylation of AKT proteins in JAR cells, it suppressed phosphorylation of the protein in JEG3 cells. In addition, we confirmed the mechanism of naringenin-induced cell signaling by using a combination of naringenin and pharmacological inhibitors of the PI3K and MAPK pathways, as well as a ROS inhibitor in JAR and JEG3 cell lines. Conclusions Collectively, results of this study indicate that naringenin is a potential therapeutic molecule with anti-cancer effects on choriocarcinoma cells by inducing generation of ROS and activation of the MAPK pathways. more...
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- 2018
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46. Approach for differentiating trophoblast cell lineage from human induced pluripotent stem cells with retinoic acid in the absence of bone morphogenetic protein 4
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Yoshihiko Hirotani, Sayaka Ohata, Hitomi Matsuda, Yoko Urashima, Arina Iwasaki, Kenji Ikeda, Saho Kishida, and Yuka Kawasaki
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0301 basic medicine ,Induced Pluripotent Stem Cells ,Retinoic acid ,Tretinoin ,Syncytiotrophoblasts ,Chorionic Gonadotropin ,Human chorionic gonadotropin ,03 medical and health sciences ,chemistry.chemical_compound ,Syncytiotrophoblast ,medicine ,Induced pluripotent stem cell ,Cells, Cultured ,reproductive and urinary physiology ,Choriocarcinoma ,Obstetrics and Gynecology ,Trophoblast ,Cell Differentiation ,medicine.disease ,Trophoblasts ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Reproductive Medicine ,Bone morphogenetic protein 4 ,chemistry ,embryonic structures ,Developmental Biology - Abstract
Introduction Placental transport is the first step in chemotherapeutic safety evaluations during pregnancy. However, a well-established in vitro model is not available. We previously reported that a trophoblast layer model using differentiating choriocarcinoma JEG-3 cells (DJEGs) can be used for placental drug transport studies. However, it was necessary to increase the similarities between the syncytiotrophoblast, the main layer of the placental barrier, and the in vitro evaluation model in order for the model to be useful for placental drug transport evaluations. We focused on in vivo similarities of differentiating induced pluripotent stem cells (iPSCs). iPSCs can achieve a syncytiotrophoblast-like form and secrete human chorionic gonadotropin (hCG) following bone morphogenetic protein 4 (BMP4) treatment. However, BMP4-treated iPSCs can differentiate into several cell types. In the placental transport model, a dense syncytiotrophoblast cell layer is necessary for appropriate differentiation. Methods The conditions permitting differentiation of iPSCs into syncytiotrophoblasts with retinoic acid (RA) treatment without BMP4 were investigated. The presence of syncytiotrophoblast-like cells was confirmed by measurement of mRNA expression levels of breast cancer resistance protein (BCRP) and paternally expressed 10 (PEG10) in syncytiotrophoblasts. In addition, immunofluorescence imaging of cytokeratin 7 (CK7) induced in trophoblasts was performed. Results and Discussion: RA-induced iPSCs exhibited these syncytiotrophoblast-like features and hCG secretion was maintained for at least 28 days after treatment with RA (500 nM) without BMP4. These results suggest that RA-induced iPSCs are a suitable in vitro syncytiotrophoblast model that can be used as an indicator of drug placental transport for pharmacotherapy during pregnancy. more...
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- 2018
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47. Secreted Frizzled Related Protein 2 Modulates Epithelial–Mesenchymal Transition and Stemness via Wnt/β-Catenin Signaling in Choriocarcinoma
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Yan Xue, Huiqiu Xu, Ruifang An, Taohong Zhang, Xianling Zeng, and Yafei Zhang
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0301 basic medicine ,Frizzled ,Epithelial-Mesenchymal Transition ,Physiology ,Dishevelled Proteins ,Down-Regulation ,Mice, Nude ,Decitabine ,lcsh:Physiology ,lcsh:Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:QD415-436 ,Epithelial–mesenchymal transition ,Choriocarcinoma ,RNA, Small Interfering ,Stemness ,Promoter Regions, Genetic ,Wnt Signaling Pathway ,Wnt/β-catenin ,lcsh:QP1-981 ,Chemistry ,Activator (genetics) ,Wnt signaling pathway ,Membrane Proteins ,Cell migration ,Transfection ,Secreted frizzled related protein 2 ,DNA Methylation ,medicine.disease ,Cell biology ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,embryonic structures ,Azacitidine ,Matrix Metalloproteinase 2 ,Female ,RNA Interference - Abstract
Background/Aims: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled-related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC’s invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC. Methods: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza-2’-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated. Results: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial-mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/β-catenin signaling, validated by the usage of a Wnt activator and inhibitor. Conclusion: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/β-catenin signaling in vitro and in vivo. more...
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- 2018
48. Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma
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Hongwei Shen, Yangshan Chen, Millicent Lin, Mengzhen Li, Liantang Wang, Yang Zhang, Cong Sun, Shijun Sun, Zunfu Ke, Han Wang, Neng Jiang, Yi Zhang, Shanyang He, Hui Zhang, Jianhong Wang, Chunlin Wang, Yongmei Cui, Manman Xu, Yu Sun, Jessica Cao, Weiling He, Minzhi Hou, Jing Liu, Chao Zeng, Xinlin Chen, and Wenting Jiang more...
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Choriocarcinoma ,Epithelial cell adhesion molecule ,medicine.disease ,Gestational choriocarcinoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Circulating tumor cell ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Biopsy ,Medicine ,Progression-free survival ,Stage (cooking) ,business - Abstract
Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5-mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non-progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with more...
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- 2018
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49. Silencing BRIT1 Facilitates the Abilities of Invasiveness and Migration in Trophoblast Cells
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Jing Zheng, Luping Liu, Li Sun, and Yanchun Wang
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0301 basic medicine ,Cell Cycle Proteins ,Nerve Tissue Proteins ,Trophoblastic Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Lab/In Vitro Research ,WNT2 ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Telomerase reverse transcriptase ,Choriocarcinoma ,Viability assay ,RNA, Small Interfering ,Wnt Signaling Pathway ,Tissue Inhibitor of Metalloproteinase-2 ,Tissue Inhibitor of Metalloproteinase-1 ,Chemistry ,Wnt signaling pathway ,Trophoblast ,General Medicine ,Transfection ,Trophoblasts ,Blot ,Cytoskeletal Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,Cell culture ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cancer research ,Matrix Metalloproteinase 2 ,Female ,Transcriptome - Abstract
BACKGROUND The improper invasion of trophoblast cells (TC) can cause various diseases. BRCT-repeat inhibitor of hTERT expression (BRIT1) is involved in the invasion of tumors. Here, we analyzed the effects of BRIT1 on the invasion of TC. MATERIAL AND METHODS The expression of BRIT1 in JEG-3, B6Tert, and HTR8/SVneo cells was evaluated by transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. The viability, invasion, and migration of HTR8/SVneo cells were measured using cell counting kit-8 (CCK-8) and Transwell assays. The activities of pro-matrix metalloproteinase-2 (pro-MMP-2) and pro-MMP-9 were tested by gelatin zymography assay. The levels of invasion- and Wnt/β-catenin pathway-related factors were assessed by RT-qPCR and Western blotting. RESULTS Levels of BRIT1 in HTR8/SVneo cells were higher than that of JEG-3 and B6Tert cells. The transfection efficiency of BRIT1 siRNA-2 was better than BRIT1 siRNA-1 in HTR8/SVneo cells. BRIT1 siRNA-2 did not change cell viability, whereas it promoted cell invasion and migration. BRIT1 siRNA-2 enhanced the activities of pro-MMP-2 and pro-MMP-9, as well MMP-2 and MMP-9 levels, and reduced tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-2 expression. Moreover, BRIT1 siRNA-2 significantly increased the levels of Wnt2, Wnt3, and β-catenin. CONCLUSIONS BRIT1 silencing accelerated the invasion and migration of TC and activated the Wnt/β-catenin pathway. Our results may provide new insights for finding new molecular targets to cure disease caused by insufficient invasion of TC. more...
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- 2018
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50. Chrysin disrupts intracellular homeostasis through mitochondria-mediated cell death in human choriocarcinoma cells
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Sunwoo Park, Wonhyoung Park, Gwonhwa Song, and Whasun Lim
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0301 basic medicine ,Programmed cell death ,MAP Kinase Signaling System ,Biophysics ,Apoptosis ,Mitochondrion ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Choriocarcinoma ,Chrysin ,Molecular Biology ,Protein kinase B ,reproductive and urinary physiology ,Cell Proliferation ,Flavonoids ,Membrane Potential, Mitochondrial ,Cell Death ,Trophoblast ,Cell Biology ,medicine.disease ,Antineoplastic Agents, Phytogenic ,female genital diseases and pregnancy complications ,Mitochondria ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,embryonic structures ,Cancer research ,Female ,Signal transduction ,Reactive Oxygen Species ,Proto-Oncogene Proteins c-akt ,Intracellular ,Signal Transduction - Abstract
The trophoblast cells which form the placenta, have a high potential for invading other tissues. Owing to certain mechanisms, trophoblast cells may lose their ability to control cell proliferation, and develop into pregnancy-related tumors, known as choriocarcinomas. Choriocarcinomas mostly develop from the hydatidiform mole, which is frequently found in pregnant women. Owing to their ability to rapidly metastasize through the hematogenous route, choriocarcinomas are very hard to cure if not detected at the proper time. Although numerous studies are attempting to identify the major pathways in choriocarcinoma cells, the critical pathway responsible for the origin of choriocarcinomas is still unclear. In this study, we identified that chrysin has inhibitory effects on human choriocarcinoma cells. The study demonstrated that chrysin disrupts intracellular homeostasis by altering the mitochondrial membrane potential (MMP), cytosolic Ca2+ levels, production of reactive oxygen species (ROS), and lipid peroxidation, leading to the death of choriocarcinoma cells (JAR and JEG3). Additionally, the effects of chrysin on choriocarcinoma cells were found to be mediated via the regulation of the AKT, ERK1/2, and JNK signaling pathways. Altogether, the anti-cancer effects of chrysin can aid the development of a novel therapeutic strategy against the progression of human choriocarcinomas. more...
- Published
- 2018
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