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Objectives: Gastric-type endocervical adenocarcinoma (GAS) is a special type of cervical adenocarcinoma that is not associated with high-risk human papilloma virus (HPV) infection, making early diagnosis challenging. This study aims to investigate the clinical characteristics, diagnosis, treatment, and prognosis of non-HPV infection-associated GAS, summarize relevant experiences, and improve the ability to recognize early lesions., Methods: A total of 21 patients with GAS treated at the Department of Gynecology, Third Xiangya Hospital of Central South University, from April 2016 to February 2023, were included. Clinical data, including age, clinical manifestations, HPV/thin-prep cytology test (TCT) results, tumor markers, imaging examinations, diagnostic methods, Federation International of Gynecology and Obstetrics (FIGO) (2018) staging, pathological results, immunohistochemistry findings, treatment, and follow-up outcomes were collected and analyzed. Kaplan-Meier method was used to calculate survival rates, log-rank test was used to calculate survival rates, log-rank test was used to compare survival differences, and Cox regression method was used to analyze prognostic factors., Results: The patients' ages ranged from 18 to 67 years [(48.4±12.0) years]. The most common initial symptom was noticeable vaginal discharge in 13 cases, followed by purulent vaginal discharge in 1 case, postmenopausal vaginal bleeding in 3 cases, bleeding during intercourse in 2 cases, prolonged menstruation in 1 case, and lower abdominal distension in 1 case. Except for 2 patients without sexual experience, the remaining patients underwent TCT and HPV testing, with 17 HPV-negative cases and 2 HPV-positive cases (1 for type 16 and 1 unclassified); TCT results were negative in 13 cases, with 2 cases of atypical squamous cells of undetermined significance (ASC-US), 1 case of atypical glandular cells-not otherwise specified (AGC-NOS), 1 case of atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H), and 2 cases of atypical glandular cells (AGC). Preoperative tumor markers were elevated in 6 of 12 cases for CA199, 4 of 21 cases for CA125, 3 of 13 cases for human epididymal protein 4 (HE4), and 1 of 19 cases for squamous cell carcinoma antigen (SCC). Among the 21 patients who underwent preoperative ultrasound, 9 cases were suspected to have cervical malignancy, and 1 case of endometrial malignancy was identified. In the 17 patients who underwent pelvic MRI, 9 cases were suspected of having cervical malignancy, along with 2 cases of endometrial malignancy. In the 9 patients who underwent pelvic CT, 7 cases were suspected of cervical malignancy. For preoperative pathology, 9 patients had a single biopsy with a confirmation rate of 33.3% (3/9), 7 patients had 2 biopsies with a confirmation rate of 71.4% (5/7), and 5 patients had 3 biopsies with a confirmation rate of 100% (5/5), leading to an overall confirmation rate of 61.9% (13/21). All patients underwent surgical treatment, with postoperative pathological staging: 3 cases at stage ⅠB1, 1 case at stage ⅠB2, 2 cases at stage ⅠB3, 1 case at stage ⅡA1, 1 case at stage ⅡA2, 2 cases at stage ⅡB, 7 cases at stage ⅢC1p, and 4 cases at stage ⅢC2p. Para-cervical infiltration was observed in 7 cases, with residual cancer at the vaginal stump in 2 cases, deep stromal infiltration (depth ≥1/2) in 19 cases, lymphovascular space invasion in 15 cases, neural invasion in 9 cases, pelvic lymph node metastasis in 11 cases, and para-aortic lymph node metastasis in 4 cases. The follow-up time ranged from 3.5 to 28.0 months (median: 13.5 months), with 13 cases not experiencing recurrence, 7 cases relapsing (6 deceased, 1 alive with tumor), and 1 case lost to follow-up. The overall survival (OS) ranged from 3.5 to 28.0 months [(22.7±1.8) months], and disease-free survival (DFS) ranged from 3.5 to 28.0 months [(20.4±2.3) months]. OS showed no correlation with age, tumor stage, tumor size, depth of stromal infiltration, lymphovascular space invasion, lymph node metastasis, or treatment method (all P >0.05). Cox regression analysis indicated that age, pathological stage, tumor size, depth of stromal infiltration, lymphovascular space invasion, neural invasion, and lymph node metastasis were not associated with DFS or OS (all P >0.05)., Conclusions: GAS is rare in clinical practice, prone to missed or misdiagnosis, with a low early diagnosis rate, strong invasiveness, high recurrence and metastasis rates, and poor prognosis. Clinicians should be vigilant for this disease in HPV-negative patients with significant vaginal discharge and consider performing multiple deep tissue biopsies in conjunction with imaging examinations for early diagnosis.

Previous studies have found that LPS and FRA1 play opposite roles in cervical cancer. In addition, LPS functions by regulating the expression of FRA1 in many disease models, but there is currently no study of their relationship in the energy metabolism of tumor cells. This study, therefore, investigates the effects of LPS on FRA1-mediated glucose metabolism and the possible mechanisms it may have in cervical cancer cells. We constructed FRA1 stable overexpressing/ empty vector cervical cancer cell lines, where glucose consumption, the level of lactic acid production and the expression of energy metabolism related molecules were detected under the stimulation of LPS. At the same time, the changes in proliferation ability of cervical cancer cells were detected. We discovered that LPS promotes glucose consumption, lactic acid production, pentose phosphate bypass, and inhibits aerobic oxidation, by inhibiting the expression of FRA1; and that LPS promotes the growth of cervical cancer cells. Our results indicate that LPS affects the proliferation and glucose metabolism of cervical cancer cells through the FRA1/MDM2/p53 pathway., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: This study on all-trans retinoic acid was designed to explore its effect on the ability of Fra-1 to cervical cancer cell development. The results show that all-trans retinoic acid enhances the effect of Fra-1 on inhibiting cervical cancer proliferation and the glucose consumption, its effect on the loss of mitochondrial membrane potential, on the decreasing of lactic acid as well as ATP, and also influences the expression of MDM2/P53/P21 and LDHA., Results: The results show that the expression of Fra-1 is higher in all-trans retinoic acid-treated cervical cancer. Flow cytometry and kit detection show that all-trans retinoic acid can enhance the ability of Fra-1 to lose the mitochondrial membrane potential, inhibit the glucose consumption and the production of lactic acid as well as ATP. CCK8 and colony formation assays indicate that all-trans retinoic acid enhances the ability of Fra-1 to inhibit cell proliferation. In addition, through Western blot analysis, it was determined that P53 and P21 were up-regulated, and MDM2 and LDHA were down-regulated., Conclusion: The overall results of the study strongly suggest that all-trans retinoic acid enhances the effect of Fra-1 on inhibiting cervical cancer proliferation and metabolism in vitro, and also influences the expression of MDM2/P53/P21 and LDHA.

Evidence has indicated the associations between thioredoxin-interacting protein (TXNIP) and cancers. However, the role of TXNIP in cervical cancer remains unclear. Hence, this study aims to investigate the role of TXNIP in regulating cervical cancer cell proliferation, migration and invasion. TXNIP expression can be regulated by either MondoA or ChREBP in a cell- or tissue- dependent manner. Thus, we also explored whether TXNIP expression in cervical cancer can be regulated by MondoA or ChREBP. Our results showed that TXNIP expression was decreased in cervical cancer cells (HeLa, SiHa, CaSki, MS751, C-33A). Furthermore, TXNIP overexpression inhibited cell proliferation, migration and invasion in HeLa cells, whereas TXNIP silencing exerted the opposite effect in C-33A cells. Moreover, TXNIP expression could be induced by MondoA, rather than ChREBP in HeLa cells. Additionally, MondoA overexpression inhibited cell proliferation, migration and invasion through upregulating TXNIP in HeLa cells. In summary, TXNIP induced by MondoA, rather than ChREBP, suppresses cervical cancer cell proliferation, migration and invasion. Our findings provide new ideas for the prevention and treatment of cervical cancer., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

BACKGROUND The aim of this study was to investigate the significance of folate receptor-mediated staining solution (FRD) in examination of cervical lesions during gynecological examination. MATERIAL AND METHODS A total of 404 patients participated in this study. FRD staining was applied to screen high grade cervical lesions. ThinPrep cytology test (TCT) and human papillomavirus (HPV) testing were also used for screening high grade cervical lesions. Coincidence rate and KAPPA value of different methods were compared by SPSS software. RESULTS As for CIN2+ and CIN3+, sensitivities for HPV testing were (96.92% and 97.78%) >TCT classification 1 (90.77% and 91.11%) >FRD staining (80.00% and 86.67%) >TCT classification 2 (70.77% and 77.78%), respectively. While specificities for HPV testing were (7.08% and 6.44%)

Cervical cancer is one of the most common malignant tumors in women all over the world. However, the exact etiology of cervical cancer remains unclear. The receptor for activated protein kinase C (RACK1) is reported to be involved in tumorigenesis and tumor progression. Besides, the prognostic value of RACK1 in several kinds of tumors has been identified. However, there are limited studies on the functional role of RACK1 in cervical cancer. In this study, we tested the expression level of RACK1 by immunohistochemistry and western blot technologies and find that it is upregulated in cervical cancer. Colony formation and CCK8 assays indicate that RACK1 promotes cell proliferation in CaSki cervical cancer cells. While the silence of RACK1 decreases the cell proliferation in CCK8 analysis. β-galactosidase staining suggests that RACK1 decreases cell senescence in cervical cancer cells. Invasion and migration assay show that RACK1 promotes the invasion and migration of cervical cancer cells. Also, when RACK1 was silenced, it exerts the opposite result. Furthermore, the mRNA expression levels of MMP‑3, MMP‑9 and MMP‑10 were upregulated in RACK1‑overexpressed CaSki cells by qPCR analysis. RACK1 also induces S phase accumulation in cell cycle analysis and suppresses cell apoptosis in cervical cancer cells. Flow cytometry analysis of mitochondria functions suggests that RACK1 increases the mitochondrial membrane potential (Δψm) levels to prevent mitochondrial apoptosis in cervical cancer cells. To explore the possible mechanism of RACK1, we tested and found that RACK1 upregulates the expression of NF-κB, cyclin D1 and CDK4 and downregulates the expression of p53, p38, p21 and STAT1 in cervical cancer cells. These results suggest that RACK1 promotes cell growth and invasion and inhibits the senescence and apoptosis in cervical cancer cells probably by affecting the p53 pathway.

Cervical cancer is one of the most common malignant tumors in women all over the world. The exact mechanism of occurrence and development of cervical cancer has not been fully elucidated. CD38 is a type II transmembrane glycoprotein, which was found to mediate diverse activities, including signal transduction, cell adhesion, and cyclic ADP-ribose synthesis. Here, we reported that CD38 promoted cell proliferation and inhibited cell apoptosis in cervical cancer cells by affecting the mitochondria functions. We established stable cervical cancer cell lines with CD38 over-expressed. CCK8 assay and colony formation assay indicated that CD38 promoted cervical cancer cell proliferation. Nude mouse tumorigenicity assay showed that CD38 significantly promotes tumor growth in vivo. CD38 also induced S phase accumulation in cell cycle analysis and suppressed cell apoptosis in cervical cancer cells. Meanwhile, flow cytometry analysis of mitochondria functions suggested that CD38 decreased intracellular Ca 2+ levels in cervical cancer cells and CD38 was involved in down-regulation of ROS levels and prevented mitochondrial apoptosis in cervical cancer cells. The percentage of cells with loss of mitochondrial membrane potential (Δψm) in CD38-overexpressed cervical cancer cells was less than control groups. Furthermore, we found an up-regulation of MDM2, cyclinA1, CDK4, cyclinD1, NF-kB P65, c-rel, and a downregulation of P53, P21, and P38 by Western blot analysis. These results indicated that CD38 enhanced the proliferation and inhibited the apoptosis of cervical cancer cells by affecting the mitochondria functions., (© 2017 Wiley Periodicals, Inc.)

Background: Previous studies have revealed the important role of miR-200b in cancer biology, including its upregulation in cervical cancer. However, miR-200b function in cervical cancer progression remains unclear. Thus, this study aims to explore the functional role of miR-200b in cervical cancer development, involving its potential regulation on FoxG1, one transcriptional repressor., Methods: Thirty paired cervical cancer samples were used to analyze the expression of miR-200b and FoxG1 by real time PCR and western blot analysis. Further gain- and loss-of-function studies were performed to validate FoxG1 as one miR-200b target, in line with luciferase report assays. MiR-200b silence was also conducted to observe its regulation on cell viability, migration and invasion in vitro, while tumor growth in vivo was tracked through the delivery of miR-200b inhibitor., Results: MiR-200b upregulation was confirmed in cancer tissues or cells as compared to normal controls, while FoxG1 downregulation was observed and then FoxG1 was definitely validated as one miR-200b target. Further in vitro studies showed that enforced miR-200b downregulation induced the decrease of cell ability, with increased cell apoptosis, and attenuated ability of cell migration and invasion in both HeLa and C33A cells, while further inhibition of FoxG1 expression could reverse all these changes. In addition, miR-200b silence in vivo strongly inhibited tumor growth., Conclusion: Upregulated miR-200b in cervical cancer was proven to show positive regulation on cervical cancer development by directly targeting FoxG1. Moreover, miR-200b silence was proposed to inhibit tumor growth in vivo, implying its therapeutic value in cervical cancer treatment., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The protein CD24 is a cell surface protein that appears to function as an adhesion molecule; its expression has been shown to correlate with prognosis in a variety of tumors. Herein, we investigated the possible role and mechanism of CD24 in cervical cancer. Our results showed that CD24 was overexpressed in cervical cancer tissues compared with that in the adjacent non‑cancerous tissues by qPCR, immunohistochemistry and western blotting technologies. To explore the possible mechanism of CD24 in cervical cancer, we elucidated the effect of CD24 on the proliferation and apoptosis of cervical cancer HeLa cells and found that a considerable increase in cell proliferation was observed in the HeLa cells with CD24 overexpession. The rate of cell apoptosis was decreased in the HeLa/CD24 cells compared with the HeLa or HeLa/vector cells. Cell apoptosis is closely related with a reduction in mitochondrial membrane potential (ΔΨm) and an increase in intracellular reactive oxygen species (ROS) and calcium ion (Ca2+) concentrations. Our results showed that overexpression of CD24 in the cervical cancer HeLa cells, led to an increase in ΔΨm and a decrease in intracellular ROS and Ca2+ concentrations. Furthermore, we found that CD24 was correlated with dysregulation of the MAPK signaling pathway in cervical cancer tissues in vitro. At the same time, we found that CD24 overexpression affected the expression of p38, JNK2 and c-Jun in vitro. In summary, our results suggest that CD24 is upregulated in cervical cancer tissues and plays its functions by affecting the MAPK signaling pathway in cervical cancer.

Objective: To investigate the effect of nano-realgar on proliferation and apoptosis of cervical cancer cells.
, Methods: Different cervical cancer cell lines (Caski/HPV16+, adeno carcinoma; Hela/HPV18+, squmous carcinoma; C33A/HPV-, adeno carcinoma) were incubated with nano-realgar at different concentrations (5, 10, 20, 40 mg/L) for different times (24, 48, 72, 96 h). The morphology was observed under phase contrast microscope. The cell viability and apoptosis were examined by MTT and flow cytometry, respectively.
, Results: The inhibitory effect of nano-realgar on the proliferation of cervical cancer cells was in a dose-dependent manner, with a range of inhibitory rate from 9.02% to 49.06%. Taking the group (20 mg/L) for an example, the inhibitory rates for Caski, Hela and C33A were 39.15%, 36.17% and 30.56%, respectively. The results of flow cytometry showed that the nano-realgar induced apoptosis in a concentration-dependent manner, with a range of apoptosis rate from 19.29% to 99.54%. Also taking the group (20 mg/L) for an example, the apoptosis rates for Caski, Hela and C33A were (60.43 ± 2.88)%, (41.95 ± 3.01)% and (43.49 ± 2.19)%, respectively. High concentration of nano-realgar (20 or 40 mg/L) could induce block of Hela and Caski at G2/M stage.
, Conclusion: Nano-realgar can inhibit the proliferation of different cervical carcinoma cell lines and can induce the cell apoptosis. The inhibitory effect on cell proliferation is strongest for Caski, followed by Hela and C33A. It can also induce G2/M stage block on HPV positive cervical cancer cells at high enough concentration.

Cervical cancer is a potentially preventable disease; however, it is the third most commonly diagnosed cancer and the fourth leading cause of cancer deaths in women worldwide. Cervical cancer is thought to develop through a multistep process involving virus, tumor suppressor genes, proto-oncogenes and immunological factors. It is known that human papillomavirus (HPV) infection is necessary but insufficient to cause malignancy. At present, the etiology of cervical carcinoma remains poorly understood. In this study, we found that the expression of FOS-like antigen-1 (Fra-1) gene was downregulated in cervical cancer compared with the adjacent non-cancerous tissues by RT-qPCR, immunohistochemistry (IHC) and western blotting techniques. To uncover the effect of Fra-1 on cervical cancer, we tested and confirmed that Fra-1 significantly inhibited the proliferation of HeLa cells by MMT assays in vitro. At the same time, overexpression of Fra-1 promoted apoptosis of HeLa cells. To explore the possible mechanism of Fra-1 in cervical cancer, we tested the expression levels of key molecules in p53 signaling pathway by western blotting technology. The results showed that p53 was downregulated in cervical cancer compared with the adjacent non-cancerous tissues, but MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) was upregulated in cervical cancer. In vitro, the p53 was upregulated and MDM2 was downregulated in HeLa cells with Fra-1 overexpression. In summary, our results suggested that Fra-1 expression is low in cervical cancer tissues and promotes apoptosis of cervical cancer cells by p53 signaling pathway.

Cervical cancer is the second most common cancer and the fifth most deadly malignancy in females worldwide, affecting 500,000 individuals each year. It is the leading cause of cancer mortality among women in developing countries. Dysregulated activation of genes, such as CD44, SOX9 and SKP2, plays a role in cervical cancer. CD38 is known to be involved in activities typical of cell surface receptors, such as signaling for activation and proliferation events and heterotypic cell adhesion. CD38 contributes to disease progression and relapse in certain tumors, such as acute myeloid and chronic lymphocytic leukemia. To the best of our knowledge, there is currently no report on the relationship between CD38 and cervical cancer. Using qPCR, immunohistochemistry, and western blot analysis, the expression levels of CD38 were investigated and found to be upregulated in cervical cancer. CD38 was correlated with dysregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in cervical cancer tissues in vitro. At the same time, CD38 overexpression affected the expression of PI3K, Akt, MDM2 and p53 in vivo. The results of the present study suggested that CD38 is highly expressed in cervical carcinoma tissues and play an important role in dysregulation of the PI3K/Akt signaling pathway.

Cervical carcinoma is the second most prevalent type of malignancy in females worldwide. The crucial etiological factors involved in the development of cervical carcinoma include infection with the papillomavirus, and the structural or functional mutation of oncogenes and tumor suppressor genes. CD44 refers to a multifunctional family of type I transmembrane proteins. These proteins have been implicated in numerous biological processes, including cell adhesion, cell migration and metastasis. The present study examined the differences in the expression levels of ATP-binding cassette sub-family G member 2, CD24, CD44, CD133, cytokeratin (CK) 14 and CK19 between cervical cancer tissues and corresponding normal non-tumor tissues by flow cytometry. Then, the CD44+ or CD44‑ cells from cervical cancer tissues were sorted for identification and confirmation of differential expression by flow cytometry. The results demonstrated that the expression level of CD44 in cervical cancer tissues was higher than in the corresponding non-tumor normal tissues (t=3.12; P=0.0102). Compared with the CD44‑ cells, the FOS-like antigen 1 (Fra-1), nestin, nuclear receptor subfamily 4, group A, member 2, OCT4 and p63 genes were highly expressed in CD44+ cells. The fold changes were 3.55, 3.55, 2.46, 2.87 and 2.56, respectively (P<0.05). However, BMI1 polycomb ring finger oncogene, ck5, tumor protein p53 and lactotransferrin genes exhibited low expression levels in CD44+ cells. It was verified by western blot analysis and flow cytometry that Fra-1 was highly expressed in CD44+ cells. Fra-1 was a potential target of miR-19a and miR-19b. The expression of miR-19a and miR-19b was downregulated by ~50% in CD44+ cells compared with CD44‑ cells. These findings suggested that CD44 dysregulated the activation of the Fra‑1 gene. The interaction of Fra-1 and CD44 may therefore be important in cervical carcinoma.

Cervical cancer remains a great problem for woman health, as it is the second deadly cancer of females worldwide. The infection of human papilloma virus (HPV) is the major risk factor for this cancer, although several other factors are also associated. Oxidative stress or antioxidant deficiency has been frequently identified to be associated with cervical cancer. Defects in the antioxidant enzyme systems are reported to play important role behind this antioxidant deficiency, which is responsible for the production of reactive oxygen species and ultimately, DNA damage in cervical cells. In response, cells become more vulnerable to HPV infection for cervical cancer development. Recently, antioxidant therapies or dietary supplementation of antioxidants have gained considerable interests in the cervical cancer treatment. In this study, we have reviewed the association of defective antioxidant systems and cervical cancer development. The recent advances in both of the basic and clinical research focusing on possible antioxidant therapy have also been discussed.