CircMUC16 promotes autophagy of epithelial ovarian cancer via interaction with ATG13 and miR-199a.

BACKGROUND: Circular RNA (circRNA) has been proven to play a significant role in multiple types of cancer. However, the expression and role of circRNAs in epithelial ovarian cancer (EOC) remains elusive. METHODS: CircRNA and mRNA expression profiles of EOC were screened with sequencing analysis. Gene silencing and over-expression were used to study circRNA function. Cell proliferation and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The expression of circRNAs, mRNAs and miRNAs was detected using qPCR. The location of circRNAs was detected using FISH. The expression of proteins was detected using western blot and immunohistochemistry. RESULTS: CircMUC16 had increased expression in EOC tissues as compared to healthy ovarian tissues. The expression of circMUC16 was linked to the progression in stage and grade of EOC. Hence, silencing circMUC16 suppressed autophagy flux of SKOV3 cells. In contrast, ectopic expression of circMUC16 promoted autophagy flux of A2780 cells. CircMUC16-mediated autophagy exacerbated EOC invasion and metastasis. Mechanistically, circMUC16 could directly bind to miR-199a-5p and relieve suppression of target Beclin1 and RUNX1. In turn, RUNX1 elevated the expression of circMUC16 via promotion of its transcription. CircMUC16 could directly bind to ATG13 and promote its expression. CONCLUSION: This study demonstrated that circMUC16 regulated Beclin1 and RUNX1 by sponging miR-199a-5p. The data suggested that circMUC16 could be a potential target for EOC diagnosis and therapy.

MiR-197 induces Taxol resistance in human ovarian cancer cells by regulating NLK.

Chemotherapy is the preferred therapeutic approach for the therapy of advanced ovarian cancer, but 5-year survival rate remains low due to the development of drug resistance. Increasing evidence has documented that microRNAs (miRNAs) act important roles in drug resistance in a variety types of cancer. However, the roles of miRNA in regulating Taxol resistance in ovarian cancer and the detailed mechanism are less reported. We used Taqman probe stem loop real-time PCR to accurately measure the levels of miR-197 in normal ovarian cells, ovarian cancer cells, and Taxol-resistant ovarian cancer cells and found that miR-197 was significantly increased in Taxol-resistant ovarian cancer cells. Enforced expression of miR-197 can promote Taxol resistance, cell proliferation, and invasion of ovarian cancer cells. Meanwhile, repression of miR-197 in ovarian cancer cells can sensitize its response to Taxol and also induced attenuated cell proliferation and invasion ability. Furthermore, investigation of the detailed mechanism showed that the promotion of miR-197 on drug resistance in ovarian cancer cells was partially mediated by downregulating NLK, a negative regulator of WNT signaling pathway. Taken together, our work first demonstrated that miR-197 can confer drug resistance to Taxol, by regulating tumor suppressor, NLK expression in ovarian cancer cells.

Alveolar Soft Part Sarcoma in the Female Genital Tract: Case Series with Literature Review and SEER Database Analysis.

Introduction: Alveolar soft part sarcoma (ASPS) is a rare and distinct subtype of soft tissue sarcoma. This study aims to describe the unique presentation of ASPS in the female genital tract. Methods: Prognostic factors for cancer-specific overall survival (CSS) were evaluated using multivariate analyses. Results: In our case series, we identified a novel TFE3-PRCC gene fusion in a 24-year-old unmarried patient with cervical ASPS who underwent fertility-sparing surgery and remained recurrence-free for 41 months. The other two patients underwent radical hysterectomy and bilateral salpingo-oophorectomy. At the time of writing, the two patients had been disease-free for 49 and 71 months, fluorescence in situ hybridization showed break-apart signals for the ASPL-TFE3 gene. Among the 55 cases with available information from the PubMed/Medline database, most presented with localized disease, and at the last follow-up, all patients were alive and 45 patients showed no evidence of disease. The 5-year CSS rate in the female genital tract cohort from SEER database was 86.2%. Multivariate analysis revealed that older age was associated with a 1.042-fold increased risk of cancer-specific mortality (HR=1.042, 95% CI 1.022-1.063, P < 0.001), involvement of soft tissue including the heart was associated with a 4.786-fold higher risk (HR=4.7868, 95% CI 1.681-13.623, P= 0.003), and regional infiltration and distant metastasis were associated with approximately 8.6-fold and 18-fold higher risk of cancer-specific mortality compared to local disease, respectively (HR=8.652, 95% CI 2.529-29.63, P = 0.001; HR=18.366, 95% CI 6.153-54.817, P< 0.001). Patients who underwent radical excision did not show reduced cancer-specific mortality compared to those who underwent local excision (HR=0.492, 95% CI 0.224-1.081, P = 0.078). Discussion: Previously unrecognized genetic diversity exists in ASPS. Patients with ASPS in the female genital tract have the lowest likelihood of presenting with a distant disease and are associated with a more favorable survival outcome.

Validation of the 2018 FIGO Staging System for Predicting the Prognosis of Patients With Stage IIIC Cervical Cancer.

Background: Risk stratification of patients with cervical cancer accompanied by positive lymph nodes (stage IIIC) (the 2018 International Federation of Gynecology and Obstetrics [FIGO] new staging system) yields a clinically heterogeneous group. In this study, we investigated the prognostic performance of the 2018 FIGO staging system for stage IIIC cervical cancer. Methods: The study included patients with stage III cervical cancer based on the 2018 FIGO staging system, who visited Chongqing University Cancer Hospital between January 2011 and December 2014. Kaplan-Meier curves were generated to evaluate overall survival (OS), which was compared using the log-rank test. The Cox proportional hazard regression model was used for multivariable analysis. Results: A total of 418 patients were eligible for analysis. The 5-year OS was 54.1% for stage IIIC1, 43.3% for stage IIIA, 40.6% for stage IIIB, and 23.1% for stage IIIC2 (P < .001). Multivariable analysis revealed that compared with stages IIIA (hazard ratio [HR] 1.432, 95% confidence interval [CI] 0.867-2.366, P = .161) and IIIB (HR 1.261, 95% CI 0.871-1.827, P = .219), stage IIIC1 cancer was not significantly associated with an increased mortality risk. Stage IIIC2 was independently associated with an increased mortality risk compared with stages IIIA (HR 2.958, 95% CI 1.757-4.983, P < .001) and IIIB (HR 2.606, 95% CI 1.752-3.877, P < .001). We stratified patients with stage IIIC1 based on the T stage. The 5-year OS was significantly longer in patients with stage IIIC1 (T1) than in those with stage IIIA (P = .004) or IIIB (P < .001). Analysis of multiple factors revealed that the mortality risk was 2.75-fold higher in patients with stage IIIC1pN>2 than in patients with stage IIIC1pN1-2 (HR 2.753, 95% CI 1.527-4.965, P = .001). Conclusions: Patients with stage IIIC1 cervical cancer showed heterogeneous clinical characteristics that reflected variable prognoses, depending on the T stage and the extent of pelvic lymph node metastases.

The myo-inositol biosynthesis rate-limiting enzyme ISYNA1 suppresses the stemness of ovarian cancer via Notch1 pathway.

Cancer stem cells (CSCs) play a central role in ovarian cancer (OC), understanding regulatory mechanisms governing their stemness is critical. Here, we report ISYNA1, the rate-limiting enzyme in myo-inositol biosynthesis, as a suppressor of OC regulating cancer stemness. We identified ISYNA1 as a differentially expressed gene in normal ovary and ovarian cancer tissues, as well as OC cells and OCSCs. Low ISYNA1 expression correlated with poor prognosis in OC patients. In addition, ISYNA1 was negatively correlated with cancer stem cell (CSC) markers, and ISYNA1-related pathways were enriched in Wnt, Notch, and other critical cancer pathways. ISYNA1 deficiency promoted OC cell growth, migration, and invasion ability in vitro and in vivo. Knockdown of ISYNA1 increased stemness of OC cells, including self-renewal, CSC markers expression, ALDH activity, and proportion of CD44+/CD117+ CSCs. Conversely, ectopic overexpression of ISYNA1 suppresses cell proliferation, migration, invasion and stemness of OC cells. Mechanistically, ISYNA1 inhibits OC stemness by regulating myo-inositol to suppress Notch1 signaling. In summary, these data provide evidence that ISYNA1 act as a tumor suppressor in OC and a regulator of stemness, providing insight into potentially targetable pathways for ovarian cancer therapy.

The effect of chemotherapy in patients with stage I mucinous ovarian cancer undergoing fertility-sparing surgery.

Objective: To determine the effect of adjuvant chemotherapy in patients with stage I mucinous ovarian cancer (MOC) undergoing fertility-preserving surgery. Patients and methods: The clinicopathological characteristics and survival information of young women with stage I MOC from SEER databases between 2004 and 2019 were collected. The relationship between chemotherapy and the characteristics was examined by univariate and multivariate logistic regression analyses. Univariable and multivariate Cox proportional hazards survival analysis were employed for cancer-specific survival. Cox analysis was performed to build a nomogram model. Results: All 901 eligible patients with stage I MOC were screened from the SEER database. There were 321(35.6%) patients aged 9-30 years, 580(64.4%) aged 31-45 years, 645 (71.6%) patients with stage IA/IB, 256 (28.4%) with stage IC disease, 411(45.6%) who underwent fertility-sparing surgery, and276(30.6%) who received postoperative adjuvant chemotherapy. Multivariate logistic regression analyses showed that postoperative chemotherapy was often used in patients aged 31-45 relative to aged 9-30 (HR: 2.215, 95%CI 1.443-3.401, P < 0.001) or with grade 3 compared to grade 1 tumors (HR: 7.382, 95%CI 4.054-13.443, P < 0.001) or with stage IC compared to stage IA/IB (HR: 6.436, 95%CI 4.515-9.175, P < 0.001) or with non-fertility sparing surgery relative to fertility-sparing (HR:2.226, 95%CI 1.490-3.327, P < 0.001). Multivariate analysis for the special population with fertility preservation indicated that patients with chemotherapy (HR: 2.905, 95% CI: 0.938-6.030, P=0.068) or with grade 3 (HR: 4.750, 95% CI: 1.419-15.896, P=0.011) had a greater risk of mortality. Significant CSS differences were observed between the non-chemotherapy and chemotherapy groups in MOC when patients were stage IA/IB-grade 2 (P=0.004) (10-year CSS rates of chemotherapy=84%, non-chemotherapy = 100%), but not when they were stage IA/IB-grade 1, stage IA/IB-grade 3 or stage IC (both P>0.05). A prognostic prediction nomogram model was built for stage I MOC patient who underwent fertility-sparing and the C-index was 0.709. Discussion: The patients aged 31-45 years, with grade 3, stage IC, and non-fertility-sparing surgery were more likely to receive adjuvant chemotherapy in the real world. For stage I MOC patient who underwent fertility-sparing surgery, the choice of chemotherapy may increase the risk of death, and it should be carefully selected in clinical practice.

Increased expression of Na+/H+ exchanger isoform 1 predicts tumor aggressiveness and unfavorable prognosis in epithelial ovarian cancer.

Na+/H+ exchanger isoform 1 (NHE1), which is a regulator of intracellular and extracellular pH via ion exchange, has been demonstrated to serve an important role in cell differentiation, migration and invasion in solid tumors and hematological malignancies. However, the potential role of NHE1 in epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression pattern and the prognostic value of NHE1 were investigated in EOC. EOC tissues, non-cancerous tumors and normal ovarian tissues were collected, and the expression levels of NHE1 were determined using the reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemistry. The expression pattern of NHE1 was also evaluated in ovarian cancer cell lines using western blotting and immunofluorescence. In addition, the association between the NHE1 expression pattern and the clinicopathological features and the clinical prognosis of patients with EOC was also analyzed. The expression levels of NHE1 were identified to be significantly increased in EOC tissues compared with non-cancerous tumors and normal ovarian tissues (P<0.05). Furthermore, the increased expression of NHE1 was associated with an advanced International Federation of Gynecology and Obstetrics stage (FIGO III-IV; P<0.001) and the presence of high-grade carcinoma (grades 2-3, P<0.001). Overexpressed NHE1 was identified as a risk factor of shorter PFS (P<0.001) and OS (P<0.001). A multivariate Cox's regression analysis revealed that NHE1 was an independent prognostic factor for the prediction of the outcome of patients with EOC. NHE1 may, therefore, serve as a potential therapeutic target to inhibit tumor aggressiveness.

Long non-coding RNA LSINCT5 promotes ovarian cancer cell proliferation, migration and invasion by disrupting the CXCL12/CXCR4 signalling axis.

Long stress-induced noncoding transcript 5 (LSINCT5) is a member of the LSINCT family, members of which are expressed during stress-induced cell formation and have also been reported to promote cancer progression. In the present study, the association between LSINCT5 expression and clinical significance was investigated and the biological function of LSINCT5 in epithelial ovarian cancer (EOC) was explored. LSINCT5 expression was examined in EOC tissues by reverse transcription-quantitative polymerase chain reaction and its association with clinicopathological factors was analysed. Cell proliferation, migration and invasion tests were performed to observe the role of LSINCT5 in human ovarian cancer cell lines in vitro. The negative control (NC) and siLSINCT5 SKOV3 cells were treated with chemokine ligand 12 (CXCL12) and their proliferation, migration and invasion activities were examined. LSINCT5 was overexpressed in EOC compared with normal ovarian tissue. LSINCT5 expression was significantly associated with the International Federation of Gynecologists and Obstetricians cancer stage and the presence of lymphatic metastases. Silencing LSINCT5 significantly reduced the expression of chemokine receptor 4 (CXCR4) and inhibited SKOV3 cell proliferation, migration and invasion, however the CXCL12 expression level had no significant change. When NC and siLSINCT5-SKOV3 cells were treated with CXCL12, the proliferation and invasion ability were significantly enhanced. The migration ability of the siLSINCT5-SKOV3 cells was also significantly enhanced. The present study indicated that LSINCT5 serves an important role in ovarian cancer metastasis by regulating the CXCL12/CXCR4 signalling axis, suggesting that this pathway may be a potential target for the treatment of patients with EOC.