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

• Published in: Molecular cancer research 2020-03, Vol.18 (3), p.436-447
• Main Authors: Xiao, Man, Guo, Jianfeng, Xie, Lisha, Yang, Chun, Gong, Lanqing, Wang, Zehua, Cai, Jing
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cisplatin - pharmacology; Disease Models, Animal; DNA Damage; DNA Repair; Down-Regulation; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Staging; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Poly (ADP-Ribose) Polymerase-1 - biosynthesis; Poly (ADP-Ribose) Polymerase-1 - genetics; Transfection
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-1369

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 PARP1. and experiments provided evidence that the let-7e-PARP1-DNA repair axis was involved in the modulation of cisplatin sensitivity in ovarian cancer. Contrary to let-7e, PARP1 was overexpressed in cisplatin-resistant ovarian cancer tissues, and patients with high PARP1 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 PARP1 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 PARP1 in ovarian cancer. IMPLICATIONS: Targeting the let-7e-PARP1-DNA repair axis might be an effective strategy for the treatment of chemoresistant ovarian cancer.