Inhibition of invasion and metastasis in choriocarcinoma by migration and invasion inhibitory protein.

INTRODUCTION: Choriocarcinoma is a highly invasive gynaecologic malignancy. Molecular mechanism of metastasis in choriocarcinoma is poorly understood. Migration and invasion inhibitory protein (MIIP) regulates cell migration and invasion. Therefore, we aimed to elucidate the function of MIIP in choriocarcinoma. METHODS: Choriocarcinoma cell lines, JAR and JEG-3, were transfected with lentivirus carrying the MIIP-interfering RNA (to downregulate MIIP expression) or left untransfected (negative control). Cell migration and invasion were studied using transwell migration assays and scratch assays. In vivo tumour burden was studied using tumour xenograft models in specific-pathogen-free nude mice and live imaging. We elucidated possible molecular signalling pathways using western blotting. RESULTS: In transwell migration and scratch assays MIIP-downregulated JAR and JEG-3 cells migrated and invaded faster compared to their respective negative control cells. Migration and invasion by the MIIP-upregulated SWAN cells was slower than that by negative control SWAN cells. Live imaging revealed that bioluminescence values were higher in MIIP-downregulated tumours than in the negative control tumours. Mice with MIIP-downregulated tumours had higher serum human chorionic gonadotropin (HCG) levels than those with negative control tumours. The MIIP expression was negatively correlated with that of histone deacetylase (HDAC6) and positively correlated with that of acetylated α-tubulin. DISCUSSION: Thus, MIIP-by inhibiting cellular motility in choriocarcinoma-acts as a tumour suppressor gene. This highlights a potential therapeutic target for refractory choriocarcinoma. Additionally, HDAC6 and acetylated α-tubulin may be involved in the regulatory effects of MIIP on the biobehaviour of choriocarcinoma cells.

PD-L1 Expression in Endometrial Serous Carcinoma and Its Prognostic Significance.

PURPOSE: Programmed death-ligand 1 (PD-L1) has been widely used as a prognostic biomarker and an immunotherapeutic target in numerous cancers, but information on the clinical significance of its expression in endometrial serous carcinoma (ESC) is largely lacking. Here, we evaluate the predictive value of PD-L1 expression in ESC. MATERIALS AND METHODS: A total of 79 cases of ESC accessioned between January 2003 and September 2015 were selected for further analysis. PD-L1 expression was evaluated in whole tissue sections of these cases by using the tumor proportion score (TPS, cut-off 1%) and combined positive score (CPS, cut-off 1) scoring methods. RESULTS: Overall, there was a heterogeneous expression of PD-L1, focal or patchy, in ESCs. PD-L1 positivity was observed in 43.0% of ESCs by TPS and 73.4% of ESCs by CPS. Kaplan-Meier survival analysis showed that patients with PD-L1-positive tumors suffered significantly worse OS and PFS, when compared with PD-L1 negative tumors (log-rank p = 0.037 and p = 0.003, respectively). In contrast, PD-L1 positivity by CPS within the ESC cases showed no statistical significance for OS and PFS (log-rank p = 0.720 and p = 0.928, respectively). Multivariate Cox analysis showed that PD-L1 positivity by TPS was significantly associated with PFS (HR = 1.921, p = 0.039) but not OS (HR = 1.229, p = 0.631). CONCLUSION: PD-L1 expression is frequently found in ESC, suggesting a potential role of the PD-1/PD-L1 pathway as a potential therapeutic target for these tumors. PD-L1 expression by TPS also serves as a negative prognostic marker in ESC and implies an unfavorable outcome.

The association between serum testosterone levels and metabolic syndrome among women.

BACKGROUND: This study aimed to investigate the relationship between total serum testosterone level (TT) and metabolic syndrome (MetS) among adult female population. Subgroup analysis further stratified the population by menopausal status to address the potential hormonal difference in postmenopausal women. METHODS: A total of 1966 participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 cycle was included for analysis in this study. MetS was defined based on the National Cholesterol Education Program Adult Treatment Panel III guidelines. Serum TT was collected during the physical examination of the NHANES program and divided into quartiles (Q) in this analysis. Menopausal status was determined based on NHANES Reproductive Health Questionnaire. Logistic regression models were applied for analysis. RESULTS: The odds of MetS in Q2: 12.99-19.38 ng/mL (OR = 0.641, 95%CI 0.493-0.835, P < 0.01), Q3: 19.39-28.38 ng/mL (OR = 0.476, 95%CI 0.362-0.626, P < 0.001), and Q4: ≥28.40 ng/mL (OR = 0.390, 95%CI 0.294-0.517, P < 0.001) were statistically lower compared to the reference Q1: <12.99 ng/mL. For the postmenopausal group, a significantly lower odds of MetS was observed in the Q2 (OR = 0.689, 95%CI 0.486-0.977, P < 0.05) and Q4 (OR = 0.606, 95%CI 0.399-0.922, P < 0.05), while the odds of Q3 (OR = 0.439, 95%CI 0.248-0.779, P < 0.01) and Q4 (OR = 0.464, 95%CI 0.261-0.825, P < 0.01) were significantly lower than the reference Q1 in the premenopausal group. CONCLUSIONS: Elevated TT levels are associated with incremental reductions in the odds of metabolic syndrome among adult females. Although, serum testosterone level is associated with the occurrence of metabolic syndrome in both the postmenopausal and the premenopausal group, the patterns of the relationship are different.

Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2.

BACKGROUND: Cancer stem cells (CSCs) are regarded as the main cell type responsible for the initiation, metastasis, drug resistance, and recurrence of cancer. But the mechanism by which cancer stem cells maintain their stemness remains unclear. METHODS AND RESULTS: In the present study, ovarian cancer stem cells (OCSCs) were revealed to have an enhanced autophagic flux. Furthermore, their chemoresistance and ability to self-renewal in vitro were decreased when autophagy was inhibited by Bafilomycin A1(BafA1), Chloroquine(CQ) or autophagy related 5(ATG5) knockdown. PCR array screening determined that Forkhead Box A2(FOXA2) was highly expressed in OCSCs, and correspondingly regulated by autophagy activity. In addition, the self-renewal ability was decreased in the case of FOXA2 knockdown by shRNA in OCSCs. Overexpression of FOXA2 from the pEGFP(+)-FOXA2 plasmid partially reversed the depressed self-renewal ability of OCSCs during autophagy inhibition. CONCLUSIONS: Our findings suggest that autophagy, through participation of FOXA2, maintains the characteristics of OCSCs. Autophagy and FOXA2 are therefore potential targets for ovarian cancer stem cell directed therapies.

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer.

Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(+)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics.