These authors contributed equally to this work.Keywords: autophagy, BECN1, ovarian cancer, paclitaxel resistance, TXNDC17Abbreviations: 95% CI, 95% confidence interval; ALDOC, aldolase C, fructose-bisphosphate; ATG5, autophagy-related 5; BafA1, bafilomycin A 1 ; BECN1, Beclin 1, autophagy-related; CNN3, calponin 3, acidic; DAPI, 4', 6-diamidino-2-phenylindole; FLNA, filamin A, a; GenMAPP, gene microarray pathway profiler; GO, gene ontology; HBSS, Hank's balanced salt solution; HR, hazard ratio; KEGG, Kyoto encyclopedia of genes and genome; LC-MS/MS, liquid chromatography-mass spectrometry/ mass spectrometry; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; OS, overall survival; PFS, progression-free survival; PGAM1, phosphoglycerate mutase 1 (brain); siRNA, short interfering RNA; SQSTM1, sequestosome 1; TNF, tumor necrosis factor; TXN, thioredoxin; TXNDC17, thioredoxin domain containing 17; UTP23, small subunit (SSU) processome component, homolog (yeast).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(C)-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.

The xenoestrogen bisphenol A (BPA) is a synthetic endocrine disrupting chemical, having the potential to increase the risk of hormone-dependent ovarian cancer. Thus, a deeper understanding of the molecular and cellular mechanisms is urgently required in the novel cell models of ovarian cancer which express estrogen receptors. To understand the possible mechanisms underlying the effects of BPA, human ovarian adenocarcinoma SKOV3 cells were exposed to BPA (10 or 100 nM) or 0.1% DMSO for 24 h, and then global gene expression profile was determined by high-throughput RNA sequencing. Also, enrichment analysis was carried out to find out relevant functions and pathways within which differentially expressed genes were significantly enriched. Transcriptomic analysis revealed 94 differential expression genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these genes related to tumorigenesis and metastasis. Further studies were carried out to validate the results of functional annotation, which indicated that BPA (10 and 100 nM) increased migration and invasion as well as induced epithelial to mesenchymal transitions in SKOV3 and A2780 cells. Accordingly, environmentally relevant-dose BPA activated the canonical Wnt signaling pathway. Our study first comprehensively analyzed the possible mechanisms underlying the effects of BPA on ovarian cancer. Environmentally relevant doses of BPA modulated the gene expression profile, promoted epithelial to mesenchymal transition progress via canonical Wnt signaling pathway of ovarian cancer.

No abstract

Previous studies have been inconsistent with respect to the reported associations between phospho-Akt (p-Akt) overexpression and lung cancer prognosis. In this study, we conducted a systematic review and meta-analysis to assess the prognostic value of p-Akt in patients with non-small cell lung carcinoma (NSCLC). Relevant articles were identified by searching MEDLINE. Hazard risks (HRs) from individual studies were calculated and pooled by using a random-effect model, and heterogeneity and publication bias analyses were also performed. Finally, 18 studies comprising 2,353 patients were included in the metaanalysis. p-Akt overexpression was associated with worse survival in NSCLC patients, and the pooled HRs for all the studies was 1.38 (95% confidence interval [CI]: 1.11-1.70; p < 0.01). After subgroup analysis, the association was strengthened in the surgery treatment group, with an HR of 1.44 (95% CI: 1.19-1.75; p < 0.01), while in the tyrosine kinase inhibitors treatment group, the statistical significance disappeared (HR: 1.22, 95% CI: 0.70-2.14; p 5 0.48). The HR in cases of early stage disease (I-III) was 1.35 (95% CI: 1.08-1.69; p 5 0.04); however, in cases of late stage disease (III-IV), the association became non-significant (HR: 1.22, 95% CI: 0.64-2.33; p 5 0.54). Our results suggest that there was a significantly inverse association between p-Akt overexpression and the prognosis of NSCLC patients, and that this association appeared to be limited in early-stage patients who underwent surgery.Lung cancer is one of the most common malignancies and the leading cause of cancer-related death worldwide.1 Nonsmall cell lung cancer (NSCLC) accounts for about 85% of all lung cancer cases, and its 5-year survival rate remains at approximately 17%, despite improvements in cancer therapies over the past few decades.2 Most recently, a number of potential prognostic markers for lung cancer have been identified, including EGFR, k-Ras, p53, ERCC1 and BRCA1.

No abstract