Let-7e Suppresses DNA Damage Repair and Sensitizes Ovarian Cancer to Cisplatin through Targeting PARP1.

Increased DNA damage repair is one of the mechanisms implicated in cisplatin resistance. Our previous study indicated that the deregulation of let-7e promoted cisplatin resistance and that let-7e could suppress DNA double-strand break repair in ovarian cancer. In this study, we further characterized the role of let-7e in DNA damage repair and cisplatin resistance in ovarian cancer, and investigated the underlying mechanisms. The alkaline and neutral comet assay indicated that let-7e impeded both DNA single- and double-strand break repairs through downregulating its target gene In vitro and in vivo experiments provided evidence that the repair axis was involved in the modulation of cisplatin sensitivity in ovarian cancer. Contrary to let-7e, was overexpressed in cisplatin-resistant ovarian cancer tissues, and patients with high Pduanyu371 expression exhibited poor progression-free survival (PFS) and overall survival (OS). Multivariate logistic and Cox regression analyses showed that let-7e and FIGO stage were independent prognostic factors for PFS and OS, whereas let-7e and Pduanyu371 were able to independently predict chemotherapy response. Taken together, our results indicated that low expression of let-7e promoted DNA single- and double-strand break repairs and subsequently contributed to cisplatin resistance by relieving the suppression on Pduanyu371 in ovarian cancer. IMPLICATIONS: Targeting the let-7e-Pduanyu371-DNA repair axis might be an effective strategy for the treatment of chemoresistant ovarian cancer.

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