ABSTRACT
The incidence of endometrial cancer has rapidly risen over recent years. Paclitaxel, a key drug for endometrial cancer treatment, inhibits microtubule depolymerization and induces apoptosis in cancer cells. Endometrial serous carcinoma (ESC) accounts for < 10% of all endometrial carcinomas, but its aggressive nature makes it responsible for close to 40% of cancer deaths. Thus, novel therapeutic targets are required for ESC. To identify microRNAs that promote paclitaxel resistance, we established two paclitaxel-resistant cell lines from USPC1 human ESC cells by exposing paclitaxel to parental cells for 12 weeks. Paclitaxel concentrations were increased every 2 weeks, and after 12 weeks of paclitaxel exposure, two replicate paclitaxel-resistant cell lines were established (USPC1-PTSR1 and USPC1-PTXR2). The microarray analysis was performed using USPC1 cells and USPC1-PTXR1 cells, and eight candidate microRNAs were thus selected as potential mediators of paclitaxel sensitivity. Among these candidate microRNAs, let-7c precursor treatment of paclitaxel-resistant USPC1-PTXR1 cells caused the greatest increase in paclitaxel-mediated cytotoxicity. Let-7c inhibition conversely decreased paclitaxel-induced apoptosis. It is known that let-7a microRNA, a member of the let-7 family, inhibits growth of endometrial carcinoma cells targeting Aurora-B that controls progression through each phase of mitosis. We thus studied whether let-7c mediates Aurora-B expression in ESC cells. The expression levels of Aurora-B mRNA and protein were higher in USPC-PTXR1 cells compared with USPC1 cells. Let-7c inhibition increased Aurora-B expression in USPC1 cells but decreased Aurora-B expression in USPC1-PTXR1 cells. These results indicate that let-7c mediates paclitaxel resistance via inhibition of Aurora-B expression in ESC cells.
Subject(s)
Aurora Kinase B/metabolism , Drug Resistance, Neoplasm/genetics , Endometrial Neoplasms/enzymology , Endometrial Neoplasms/genetics , MicroRNAs/metabolism , Neoplasms, Cystic, Mucinous, and Serous/enzymology , Neoplasms, Cystic, Mucinous, and Serous/genetics , Paclitaxel/pharmacology , Apoptosis/drug effects , Aurora Kinase B/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Endometrial Neoplasms/drug therapy , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MicroRNAs/genetics , Molecular Targeted Therapy , Neoplasms, Cystic, Mucinous, and Serous/drug therapy , Paclitaxel/therapeutic useABSTRACT
OBJECTIVE: The present study aimed to clarify the clinicopathological features, including the level of p53 protein expression and BRCA mutations, of primary fallopian tube cancer (PFTC) in Japanese women. METHODS: A multicenter clinical survey was conducted at three Japanese institutions. Clinical data in patients with PFTC between 1998 and 2016 were collected. Immunohistochemical staining of p53 and BRCA mutation analysis by exome sequence using paraffin-embedded surgical resected specimens were performed. RESULTS: A total of 40 patients with PFTC were enrolled in the study. The median age was 58 years (range: 38-78 years); 31 patients were menopausal. Thirty-four (85.0%) patients were diagnosed with serous adenocarcinoma (high grade, 33; low grade, 1). PFTC was classified into ampulla type, fimbriae type and undeterminable type by tumor-occupying lesion; ampulla type and fimbriae type occurred with the same frequency. Among 30 patients with high-grade serous adenocarcinoma, 6 patients showed germline mutations of BRCA1 (stop-gain 4 and frameshift deletion 2) and 2 patients showed germline mutation of BRCA2 (stop-gain 1 and frameshift deletion 1). However, only 1 patient had familial history of breast or ovarian cancer. Patients with BRCA mutations in the germline were frequently observed in ampulla type and FIGO stage I/II cancers, but no significant difference in the frequency of p53 overexpression and overall survival was observed. CONCLUSIONS: Among Japanese patients with PFTC, 26.7% presented with BRCA mutations in the germline. Additionally, p53 was important for the carcinogenesis in fallopian tubes, independent of the specific BRCA mutation.
Subject(s)
Asian People/genetics , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Fallopian Tube Neoplasms/genetics , Fallopian Tube Neoplasms/pathology , Mutation/genetics , Adult , Aged , Cystadenocarcinoma, Serous/genetics , Fallopian Tubes/pathology , Female , Humans , Middle AgedABSTRACT
BACKGROUND: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS)). METHODS: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed. RESULTS: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS. CONCLUSIONS: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.
