Abstract
Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (paclitaxel; TX) is widely used for ovarian cancer treatment. However, ovarian cancers often acquire chemoresistance. MicroRNAs (miR) have been reported to mediate many tumours’chemoresistance. We investigated the role of miR-363 in the chemoresistance of the ovarian cancer cell line, KF, and its TX-resistant derivative (KF-TX) cells. QRT-PCR indicated that miR-363 was upregulated in KF-TX cells, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assay and expression analysis. Furthermore, we validated the role of LATS2 in TX-response by sh-based silencing, which also confers TX-resistance to the ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX in the resistant cells. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while it was downregulated in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.
Highlights
Epithelial ovarian cancer is the most frequent cause of gynaecologic malignancy-related mortality in women [1, 2] because 75% of ovarian cancers are detected as late-stage disease [3]
Our study reveals the involvement of miR363 in chemoresistance by targeting large tumor suppressor 2 (LATS2) in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance
We focused our study on those with tumour suppression function or those with drug www.oncotarget.com metabolism-related functions, including RE1-silencing transcription factor (REST), sperm Associated Antigen 6 (SPAG6), phosphatase and tensin homolog deleted from chromosome 10 (PTEN), frizzled-1 (FZD1) and large tumor suppressor 2 (LATS2)
Summary
Epithelial ovarian cancer is the most frequent cause of gynaecologic malignancy-related mortality in women [1, 2] because 75% of ovarian cancers are detected as late-stage disease [3]. Optimal surgical debulking of the tumour (no residual disease) followed by chemotherapy is the standard regimen for advanced cases [4]. Even after achieving clinical remission, most patients with advanced epithelial ovarian cancer will develop recurrent disease [6]. MiRNAs expression have been reported in a variety of human cancers versus normal, including ovarian cancer [8, 9, 10, 11]. MiRNAs regulate cellular apoptosis, expression of multiple drug resistance (MDR)related proteins and induction of cancer cell conversion to tumour stem-like cells (TSCs) in several cancers [15]. The role of some miRNAs in the acquisition of drug resistance in ovarian cancer cells had been reported [16, 17] the role of many miRNAs is still elusive
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
