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.

Paclitaxel is widely used as a first-line chemotherapeutic drug for patients with ovarian cancer and other solid cancers, but drug resistance occurs frequently, resulting in ovarian cancer still presenting as the highest lethality among all gynecological tumors. Here, using DIGE quantitative proteomics, we identified UBC13 as down-regulated in paclitaxel-resistant ovarian cancer cells, and it was further revealed by immunohistochemical staining that UBC13 low-expression was associated with poorer prognosis and shorter survival of the patients. Through gene function experiments, we found that paclitaxel exposure induced UBC13 down-regulation, and the enforced change in UBC13 expression altered the sensitivity to paclitaxel. Meanwhile, the reduction of UBC13 increased DNMT1 levels by attenuating its ubiquitination, and the up-regulated DNMT1 enhanced the CHFR promoter DNA methylation levels, leading to a reduction of CHFR expression, and an increased in the levels of Aurora A. Our findings revealed a novel function for UBC13 in regulating paclitaxel sensitivity through a DNMT1-CHFR-Aurora A pathway in ovarian cancer cells. UBC13 could potentially be employed as a therapeutic molecular drug for reversing paclitaxel resistance in ovarian cancer patients.

To investigate the CpG island methylation and the mRNA expression of OPCML gene in patients with cervical carcinoma, we collected tumor and stroma cells from 36 invasive cervical carcinoma samples and 16 normal cervical tissues as well as Hela cells. Methylation specific PCR was used to detect promoter CpG island methylation status, and fluorescence quantitative RT-PCR was used to detection of OPCML gene expression. Our data showed that OPCML gene promoter methylation may play an important role in the carcinogenesis of cervical carcinoma and OPCML gene may be a cervical carcinoma-associated candidate TSG (tumor suppressor gene).