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.
Highlights
Resistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment
We provided evidence supporting the involvement of let-7e in double strand break (DSB) repair and cisplatinresistance and explored the prognostic values of let-7e and two key factors implicated in homologous recombination (HR) repair, BRCA1 and Rad51, for survival and chemo-response in epithelial ovarian cancer (EOC)
Let-7e is correlated with chemo-resistance in epithelia ovarian cancer To determine whether let-7e plays a role in the generation of chemotherapy resistance in EOC, we compared let-7e expression in chemo-resistant EOC (n = 22) versus chemo-sensitive EOC (n = 43) using in situ hybridization (ISH)
Summary
Resistance to platinum-based chemotherapy remains a great challenge for ovarian cancer treatment. Our previous study showed that deregulation of let-7e in epithelial ovarian cancer (EOC) promoted the development of resistance to cisplatin. Platinum drugs are the most widely used first-line chemotherapy agents for treatment of epithelial ovarian cancer (EOC), which exert cytotoxic effect through reacting with DNA. Emerging data suggest that let-7 family members display different activities, and most members have been implicated in the modulation of drug sensitivity in cancers [10]. We provided evidence supporting the involvement of let-7e in DSB repair and cisplatinresistance and explored the prognostic values of let-7e and two key factors implicated in HR repair, BRCA1 and Rad, for survival and chemo-response in EOC
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