title: MiR-490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2.
abstract: Cisplatin (CDDP) resistance becomes a large obstacle of the beneficial therapy for patients with ovarian cancer. MicroRNAs (miRNAs) act as post-transcriptional regulators of multiple genes' expression and have been reported to be involved in multi-drug resistance. The purpose of this study was to determine the roles and molecular mechanism of miR-490-3p in the CDDP resistance in ovarian cancer. We found that miR-490-3p was downregulated in CDDP-resistant OVCAR3/CDDP and SKOV3/CDDP cells, which was due to the hypermethylation of miR-490-3p promoter. Functional studies demonstrated that miR-490-3p increased the cell response to CDDP in OVCAR3, SKOV3 and CDDP-resistant cells, while miR-490-3p inhibition resulted in opposite effects. Luciferase assay, real-time PCR and Western blot as well as immunohistochemistry validated that ABCC2 was a direct target of miR-490-3p and miR-490-3p downregulated ABCC2 expression via binding to its 3'UTR. Importantly, silencing of ABCC2 alleviated CDDP resistance induced by miR-490-3p inhibition, while ABCC2 overexpression restored CDDP resistance inhibited by miR-490-3p. In vivo study showed that miR-490-3p enhanced the cytotoxicity of CDDP. Finally, we found that miR-490-3p was downregulated in CDDP-resistant ovarian cancer tissues, while ABCC2 was upregulated. In conclusion, our data indicate that miR-490-3p enhances CDDP sensitivity of ovarian cancer cells through downregulating ABCC2 expression, and suggest that delivery of miR-490-3p might be a potential therapeutic strategy for patients with CDP-resistant ovarian cancer.
authors.affiliation: Department of Gynecology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Gynecology, The Second Hospital of Tianjin Medical University Tianjin 300060, China.
authors.forename: Yan-Ying
authors.initials: YY
authors.lastname: Xu
authors.affiliation: Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Gynecology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Huan-Hu-Xi Road, Ti-Yuan-Bei, He Xi District, Tianjin 300060, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
keywords: ABCC2; CDDP sensitivity; MicroRNA; miR-490-3p; ovarian cancer