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Xi Su,1 Jiaxin Liu,1 Haihong Zhang,1 Qingqing Gu,1 Xinrui Zhou,1 Meiju Ji,2 Demao Yao3 1Key Laboratory for Tumor Precision Medicine of Shaanxi Province, Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 2Center for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of China; 3Department of Geriatric Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, People’s Republic of ChinaCorrespondence: Demao YaoDepartment of Geriatric Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, No. 266, Yanta West Road, Xi’an 710061, People’s Republic of ChinaTel/Fax +86 13991953123Email ydm_723@163.comMeiju JiCenter for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, No. 266, Yanta West Road, Xi’an 710061, People’s Republic of ChinaTel/Fax +86 29 8532 3259Email mjji0409@163.comPurpose: Anaplastic thyroid cancer (ATC) is a kind of rare thyroid cancer with very poor prognosis. Doxorubicin has been approved in ATC treatment as a single agent, but monotherapy still shows no improvement of the total survival in advanced ATC. Lenvatinib was investigated with encouraging results in treating patients with radioiodine-refractory differentiated thyroid cancer (DTC). However, antitumor efficacy of combination therapy with lenvatinib and doxorubicin remains largely unclear.Materials and Methods: The antitumor efficacy of combination therapy with lenvatinib and doxorubicin on ATC cell proliferation was assessed by the MTT assay and colony formation. Flow cytometry was employed to assess ATC cells’ apoptosis and cell cycle arrest in response to combination therapy. Transwell assay was used to test the migration and invasion in response to combination therapy. Xenograft models were used to test its in vivo antitumor activity.Results: Lenvatinib monotherapy was less effective than doxorubicin in treating ATC cell lines and xenograft model. The combination therapy of lenvatinib and doxorubicin significantly inhibited ATC cell proliferation and tumor growth in nude mice, and induced cell apoptosis and cell cycle arrest as compared to lenvatinib or doxorubicin monotherapy.Conclusion: Lenvatinib promotes the antitumor effect of doxorubicin in ATC cell and xenograft model. The lenvatinib/doxorubicin combination may be a potential candidate therapeutic approach for anaplastic thyroid cancer.Keywords: anaplastic thyroid cancer, lenvatinib, doxorubicin, combining therapy

Rui Chen, Yan Chen, Weiqing Zhao, Cheng Fang, Wenjie Zhou, Xin Yang, Mei Ji Department of Oncology, The Third Affiliated Hospital of Soochow University, The First People’s Hospital of Changzhou, Changzhou 213003, People’s Republic of ChinaCorrespondence: Xin Yang; Mei Ji Email yangxindoctor@163.com; zlkjimei@163.comAbstract: Malignant solid tumors are the leading cause of death in humans, and epigenetic regulation plays a significant role in studying the mechanism of human solid tumors. Recently, histone lysine methylation has been demonstrated to be involved in the development of human solid tumors due to its epigenetic stability and some other advantages. The 90-kb protein methyltransferase nuclear receptor SET domain-containing 2 (NSD2) is a member of nuclear receptor SET domain-containing (NSD) protein lysine methyltransferase (KMT) family, which can cause epigenomic aberrations via altering the methylation states. Studies have shown that NSD2 is frequently over-expressed in multiple types of aggressive solid tumors, including breast cancer, renal cancer, prostate cancer, cervical cancer, and osteosarcoma, and such up-regulation has been linked to poor prognosis and recurrence. Further studies have identified that over-expression of NSD2 promotes cell proliferation, migration, invasion, and epithelial–mesenchymal transformation (EMT), suggesting its potential oncogenic role in solid tumors. Moreover, Gene Expression Profiling Interactive Analysis (GEPIA) was searched for validation of prognostic value of NSD2 in human solid tumors. However, the underlying specific mechanism remains unclear. In our present work, we summarized the latest advances in NSD2 expression and clinical applications in solid tumors, and our findings provided valuable insights into the targeted therapeutic regimens of solid tumors.Keywords: NSD2, proliferation, migration, invasion, EMT, oncogene

Qian Liu,1,2 Wei Li,1 Ying Zhou,1 Jimo Jian,1,3 Shijie Han,4 Chao Liu,5 Wei Li,1 Xunxun Zhu,6 Daoxin Ma,1,7 Min Ji,1 Chunyan Ji1 1Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China; 2Department of Pain, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China; 3Department of Hematology, Qilu Hospital, Shandong University (Qingdao), Qingdao 266000, People’s Republic of China; 4Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, People’s Republic of China; 5Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, People’s Republic of China; 6Department of Hematology, Tengzhou Central People’s Hospital, Tengzhou 277599, People’s Republic of China; 7Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of ChinaCorrespondence: Min JiDepartment of Hematology, Qilu Hospital, Shandong University, West Wenhua Road, Jinan 250012, People’s Republic of ChinaEmail jimin@sdu.edu.cnIntroduction: Progression and chemoresistance of acute myeloid leukemia (AML) contribute to most of the treatment failure. Notch pathway has been proven to be involved in many biological processes and diseases, especially AML. In this study, we aimed to explore genes correlated with Notch1 pathway in AML and determine their roles in the regulation of AML progression and chemoresistance.Methods: TCGA database was used to explore Notch1 associated genes. Kaplan–Meier survival analysis was performed to evaluate the prognostic significance of genes. Quantitative RT-PCR (qRT-PCR) and Western blot were performed to examine the expression of genes. The expression of PRKD2 was up-regulated or knocked down in AML cell lines by lentivirus or siRNAs. CCK-8 and flow cytometry were used to analyze the effect of PRKD2 on cell proliferation and chemoresistance.Results: Based on TCGA database, PRKD2 was found to be positively correlated with Notch1 expression, cytogenetic risk status and poorer prognosis in AML. Moreover, the expression level of PRKD2 was higher in AML chemo-resistant cells than in chemo-sensitive cells. Functionally, knockdown of PRKD2-induced apoptosis and increased chemosensitivity of AML cells. PRKD2 overexpression promoted proliferation and chemoresistance of AML cells. Furthermore, we found PRKD2 could regulate Notch1 pathway. Besides, high PRKD2 expression was correlated with higher risk group of AML patients which indicated that PRKD2 was an independent prognostic marker for AML.Conclusion: Taken together, our results showed that PRKD2 could promote the proliferation and chemoresistance of AML cells by regulating Notch1 pathway. The study broadened our insights into the underlying mechanisms in chemoresistance and proliferation of AML, and provided a new prognostic marker and treatment target for AML.Keywords: PRDK2, AML, progression, chemoresistance, Notch1

Peifen Zheng, Weifeng Wang, Muxi Ji, Qin Zhu, Yuliang Feng, Feng Zhou, Qiaona He Department of Gastroenterology, Zhejiang Hospital, Hangzhou, People’s Republic of China Objective: TMEM119 is a member of transmembrane proteins family, which is abnormally expressed in human cancers and associated with tumorigenesis. In this study, we focused on the expression of TMEM119 and its role in cell invasion and migration in gastric cancer. Methods: Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed to examine the expression of TMEM119 in gastric cancer tissues and cell lines. After transfection with TMEM119 siRNA or recombined TMEM119-expressing vector, the invasion and migration ability of MKN45 and SGC-7901 cells was measured by transwell assay. The expression of TMEM119, p-STAT3, STAT3, VEGF, MMP2, and MMP9 proteins in SGC-7901 and MKN45 cells treated with TMEM119 siRNA, TMEM119-expressing vector, or AG490 was measured by Western blotting. Results: We found that higher TMEM119 expression was found in gastric cancer tissues and cell lines and was associated with lower survival rate. TMEM119 knockdown inhibited SGC-7901 cell invasion and migration, along with the expression of p-STAT3, VEGF, MMP2, and MMP9. TMEM119 overexpression promoted MKN45 cell invasion and migration, along with the expression of p-STAT3, VEGF, MMP2, and MMP9. Additionally, AG490 treatment significantly corrected TMEM119-induced MKN45 cell migration and invasion and expression of p-STAT3, VEGF, MMP9, and MMP2 proteins. Conclusion: The results indicated that TMEM119 promotes gastric cancer cell migration and invasion through activation of STAT3 signaling pathway, and TMEM119 may therefore act as a novel therapeutic target for gastric cancer. Keywords: gastric cancer, TMEM119, migration, invasion, STAT3, VEGF, MMP2, MMP9

Xin Yang, Rui Chen, Chen Wu, Weiqing Zhao, Mei Ji Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China Abstract: Rapid metastasis contributes significantly to the high mortality rates in lung adenocarcinoma. The present study reports a rare case of primary lung adenocarcinoma with concomitant gastric, duodenal, bone, and mediastinal lymph node metastases. A large gene panel based on the next-generation sequencing was used to detect gene mutations in different metastatic sites and blood. The results showed that the gene mutation spectrums among different metastatic foci were roughly similar. The mutation abundance was highest in mediastinal lymph nodes. Unique mutation sites were detected only in mediastinal lymph nodes, bone, and gastric metastatic foci. Despite partial heterogeneity, there are currently no applicable targeted drugs to adopt. In addition, tumor mutation burden (TMB) showed that blood, gastric, bone, and mediastinal lymph node metastases were all TMB-High, while the duodenal metastasis was TMB-Low. This study is the first to report a rare case of newly diagnosed lung adenocarcinoma with concomitant gastrointestinal metastases and to perform mutation analyses on all metastatic foci. Large sample sizes with similar cases are required to gain deeper insights. Keywords: lung adenocarcinoma, gastric metastasis, duodenal metastasis, TMB

Ming Ji,1 Liyuan Wang,1 Ju Chen,1 Nina Xue,2 Chunyang Wang,2 Fangfang Lai,2 Rubing Wang,1 Shishan Yu,1 Jing Jin,1,2 Xiaoguang Chen1,2 1State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China; 2Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China Purpose: Glioblastoma multiforme (GBM) is a malignant high-grade glioma with a poor clinical outcome. Temozolomide (TMZ) is the first-line GBM chemotherapy; however, patients commonly develop resistance to its effects. Materials and methods: We investigated the antitumor activity of CAT3 in TMZ-resistant glioblastoma cell lines U251/TMZ and T98G. Orthotopic and subcutaneous mice tumor models were used to investigate the effects of various treatment regimes. Results: We found that PF403, the active metabolite of CAT3, inhibited proliferation of both cell lines. PF403 repressed the Hedgehog signaling pathway in the U251/TMZ cell line, reduced O6-methylguanine DNA methyltransferase (MGMT) expression, and abolished the effects of the Shh pathway. Moreover, PF403 blocked the Hedgehog signaling pathway in T98G MGMT-expressing cells and downregulated the expression of MGMT. CAT3 suppressed growth in the U251/TMZ orthotopic and T98G subcutaneous xenograft tumor models in vivo. We also demonstrated that inhibition of the Hedgehog pathway by PF403 counteracted TMZ resistance and enhanced the antitumor activity of TMZ in vitro and in vivo. Conclusion: These results indicate that CAT3 is a potential therapeutic agent for TMZ-resistant GBM. Keywords: Gli inhibitor, chemotherapy, lomeguatrib, xenograft tumor model

Wentao Tang,* Meiling Ji,* Guodong He,* Liangliang Yang, Zhengchuan Niu, Mi Jian, Ye Wei, Li Ren, Jianmin Xu Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: An increasing number of studies have demonstrated that circular RNAs (circRNAs) can regulate gene expression through interacting with microRNAs. In this study, we analyzed the expression of antisense to CDR1as in colorectal cancer (CRC). CDR1as had a higher expression in CRC tissues compared to adjacent, normal mucosa and was positively associated with tumor size, T stage, lymph node metastasis, and poor overall survival (OS). Downregulation of CDR1as suppressed CRC cell proliferation and invasion and increased microRNA-7 (miR-7) expression. Intriguingly, ectopic expression of miR-7 in CRC cells consistently inhibited proliferation and invasion, and the miR-7 inhibitor was able to rescue the function of CDR1as knockdown. Mechanistic studies demonstrated that CDR1as silencing suppressed EGFR and IGF-1R expression, which could be partially blocked by the miR-7 inhibitor. Finally, positive correlations between CDR1as expression and EGFR and IGF-1R expression were observed in CRC samples. Thus, given the importance of CDR1as in blocking miR-7 and positively regulating EGFR and IGF-1R, dysregulated CDR1as expression may play an important role in CRC progression. Keywords: CDR1as, colorectal cancer, microRNA-7, proliferation

Chunzhi Qin,1,* Li Ren,1,* Meiling Ji,1,* Shixu Lv,2,* Ye Wei,1 Dexiang Zhu,1 Qi Lin,1 Pingping Xu,1 Wenju Chang,1 Jianmin Xu1 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 2Department of Surgical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally to this work Background: CDKL1 is a member of the cell division cycle 2 (CDC2)-related serine threonine protein kinase family and is overexpressed in malignant tumors such as melanoma, breast cancer, and gastric cancer.Objective: This study aimed to evaluate whether CDKL1 can serve as a potential molecular target for colorectal cancer therapy.Materials and methods: Expression of CDKL1 in colorectal cancer tissues and cell lines was measured by immunohistochemistry and Western blot, respectively. To investigate the role of CDKL1 in colorectal cancer, CDKL1-small hairpin RNA-expressing lentivirus was constructed and infected into HCT116 and Caco2 cells. The effects of RNA interference (RNAi)-mediated CDKL1 downregulation on cell proliferation and invasion were assessed by CCK-8, colony formation, transwell, and tumorigenicity assays in nude mice. The effects of CDKL1 downregulation on cell cycle and apoptosis were analyzed by flow cytometry. Furthermore, microarray method and data analysis elucidated the molecular mechanisms underlying the phenomenon.Results: CDKL1 protein was overexpressed in colorectal cancer tissues compared with paired normal tissues. Knockdown of CDKL1 in HCT116 and Caco2 significantly inhibited cell growth, colony formation ability, tumor invasion, and G1–S phase transition of the cell cycle. The knockdown of CDKL1 stimulated the upregulation of p15 and retinoblastoma protein.Conclusion: CDKL1 plays a vital role in tumor proliferation and invasion in colorectal cancer in vitro and in vivo and, thus, may be considered as a valuable target for therapeutic intervention. Keywords: CDKL1, cell cycle, protein kinases, colorectal cancer

Qi Lin,# Ye Wei,# Li Ren,# Yunshi Zhong,# Chunzhi Qin, Peng Zheng, Pingping Xu, Dexiang Zhu, Meiling Ji, Jianmin XuDepartment of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China#These authors contributed equally to this workBackground: Tumor deposits are one of the important influencing factors among the different editions of Tumor, Node, Metastasis classification. Incidence and prognosis of tumor deposits in stage I, II, and III colorectal cancer patients has been explored. The aim of this study was to determine the prognostic value of tumor deposits in stage IV colorectal cancer patients who underwent simultaneous resection for synchronous colorectal liver metastases (SCRLM).Methods: Clinicopathological and outcome data of 146 consecutive SCRLM patients who underwent simultaneous R0 resection between July 2003 and July 2013 were collected from our prospectively established SCRLM database. The prognostic value of tumor deposits was evaluated by Kaplan–Meier and Cox regression analysis.Results: Tumor deposits were detected in 41.8% (61/146) of these SCRLM patients. Tumor deposits were significantly correlated with lymph node metastasis and nerve invasion of the primary tumors (P=0.002, P=0.041; respectively). The Kaplan–Meier survival analysis revealed that the overall survival (OS) and disease-free survival (DFS) of SCRLM patients with tumor deposits were significantly poorer than those with no tumor deposits (P=0.039, P=0.001; respectively). And with multivariate analysis, we found that positive tumor deposits were significantly associated with shorter DFS independent of lymph node status (P=0.002). Subgroup analysis found that of the 57 SCRLM patients with negative lymph node status, the OS and DFS of patients with positive tumor deposits were significantly shorter than those with negative tumor deposits (P=0.002 and P=0.031, respectively). Of the 89 patients with positive lymph node status, the OS of patients with tumor deposits was not significantly different than those without tumor deposits (P=0.965); however, the DFS of patients with tumor deposits was significantly shorter than those with no tumor deposits (P=0.034).Conclusion: Tumor deposits may be an independent adverse prognostic factor in SCRLM patients who underwent simultaneous R0 resection.Keywords: tumor deposits, synchronous colorectal liver metastases, prognostic factors&nbsp

Mingliang Ji,1 Yan Lu,1 Lina Guo,2 Fengzhi Feng,1 Xirun Wan,1 Yang Xiang1 1Department of Obstetrics and Gynecology, 2Department of Pathology, Peking Union Medical College Hospital, Beijing, People's Republic of China Abstract: Endometrial carcinoma with a germ cell tumor component is a rare event. Here we report a uterine neoplasm with a unique combination of endometrioid adenocarcinoma and mixed germ cell malignant elements. A 28-year-old woman with abnormal vaginal bleeding, an abdominal mass, and elevated alfa-fetoprotein and beta-human chorionic gonadotropin (ß-hCG) levels had a history of biopsy of an omental mass and chemotherapy in another hospital one month before her referral to our department. Histologic examination of the mass removed from the omentum revealed an endometrioid adenocarcinoma with yolk sac tumor-like differentiation. Total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, and removal of metastatic disease were then undertaken at our hospital. Postoperative chemotherapy was given. Eight months postoperatively, serum alfa-fetoprotein and ß-hCG rose again. Cases with primary yolk sac tumors of the endometrium or endometrial carcinoma with trophoblastic differentiation in the literature were reviewed. Keywords: endometrial carcinoma, yolk sac tumor, trophoblastic differentiation