Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair

Abstract

BackgroundResistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. The human let-7 family contains 13 members located on nine different chromosomes, and most members have been implicated in the modulation of drug sensitivity in cancers. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. In the present study, we aimed to investigate the underlying mechanism and further evaluate the clinical value of let-7e in predicting chemo-response and prognosis in EOC.ResultsIn situ hybridization assays revealed a significantly decreased expression of let-7e in chemo-resistant EOC tissues compared with chemo-sensitive cases. Transfection with let-7e agomir sensitized EOC cells to cisplatin, down-regulated BRCA1 and Rad51 expression, and repressed the repair of cisplatin-induced DNA double strand break, while let-7e inhibitor exerted the opposite effects. In human EOC tissues, BRCA1 and Rad51 levels were increased in the chemo-resistant group compared with the sensitive group and were negatively correlated with let-7e. Low let-7e and high Rad51 were significantly associated with poor progression-free survival and overall survival and multivariate regression analyses showed that let-7e was an independent predictor for overall survival and chemotherapy response in EOC. Receiver operating characteristic analysis indicated that let-7e level was highly predictive of resistance to platinum-taxane chemotherapy with an area under the curve of 0.826.ConclusionsIn EOC, low let-7e leads to activation of BRCA1 and Rad51 expression and subsequent enhancement of DSB repair, which in turn results in cisplatin-resistance. Let-7e is a potential predictor for survival and chemo-response in EOC and re-expression of let-7e might be an effective strategy for overcoming chemo-resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s13048-017-0321-8) contains supplementary material, which is available to authorized users.

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

“…; Qilu Pharma, Shandong, China) combined with liposomal paclitaxel (135‐175 mg/m 2 , i.v. ; Luye Pharma Group, Jiangsu, China) every 3 weeks for six cycles was used . Chemoresistance is characterized by tumors that show no response to chemotherapy (stable disease), progression during chemotherapy, or chemotherapy relapse within 6 months of the completion of primary chemotherapy .…”

The Drug-Resistance Mechanisms of Five Platinum-Based Antitumor Agents

“…Other than ERCC and BRCA, many key components like FANCD2 (Martens-de Kemp et al, 2017), PCNA (Somasagara et al, 2017), XRCC1 (Xu et al, 2014), and RAD51 (Pan et al, 2013b;Xiao et al, 2017), also play different roles in multiple DNA repair pathway. A better understanding of the DNA repair regulation network will provide a more accurate guide to personalized platinum-based chemotherapy.…”

The potential role of miRNAs and exosomes in chemotherapy in ovarian cancer

“…Mutation in BRCA1 contributes to resistance to chemotherapy. In situ hybridization, immunoblotting and transfection assays were used to investigate the expression and function of let-7e in epithelial ovarian cancer tissues and cells and their response to cisplatin (Xiao et al 2017).…”