MiR-489 modulates cisplatin resistance in human ovarian cancer cells by targeting Akt3

Abstract

MicroRNAs are a conserved class of small noncoding RNA molecules that harbour the capacity to regulate protein-coding gene expression at the post-transcriptional level. In the current study, we show that miR-489 is downregulated in cisplatin (CDDP)-resistant ovarian cancer cells, SKOV3/CDDP and OVCAR3/CDDP cells. MiR-489 overexpression results in an inhibition of SKOV3 and OVCAR3 cell survival and cell growth after CDDP treatment and an induction of cell apoptosis. Inhibition of miR-489 yields the opposite results. In addition, miR-489 overexpression increases the sensitivity of SKOV3/CDDP and OVCAR3/CDDP cells to CDDP and inhibits their colony number. Akt3 is validated as a direct target of miR-489 in SKOV3, OVCAR3, SKOV3/CDDP and OVCAR3/CDDP cells. In addition, miR-489 suppresses Akt3 protein expression by binding sites on its 3'UTR. Knockdown of Akt3 results in a similar effect as that because of miR-489 overexpression; importantly, Akt3 silencing rescues the functions induced by miR-489. Furthermore, we also use the Akt3 inhibitor, MK-2206 2HCl, to determine the role of Akt3 in CDDP resistance. Our study showed that MK-2206 2HCl increased the sensitivity of SKOV3/CDDP and OVCAR3/CDDP cells to CDDP. Taken together, our results indicate that miR-489 inhibited CDDP resistance and cell growth, and promotes apoptosis by suppressing Akt3 expression. Furthermore, the identification of a novel miR-489-based pathway in CDDP-resistant ovarian cancer will facilitate the development of therapeutic strategies.

Novel RNA biomarkers of prostate cancer revealed by RNA-seq analysis of formalin-fixed samples obtained from Russian patients

“…These 3′-UTR motifs are recognized by the following microRNAs: miR-527, miR-374, miR-520F, miR-513, miR-142-5p, miR-507, miR-369-3p, miR-491, miR-511, miR-489, miR-432, miR-28, miR-520G and miR-520H. It is worth noting that every microRNA from this set had been associated with other oncological diseases including breast [33–36], ovarian [37, 38], colorectal cancers [39–41], glioblastoma [42, 43], non-small cell lung cancer [44, 45] and others.…”

LncRNA CHRF-induced miR-489 loss promotes metastasis of colorectal cancer via TWIST1/EMT signaling pathway

“…Furthermore, miR-489 functions as a tumor suppressor in hypopharyngeal squamous cell carcinoma and suppresses growth of cancer cells by targeting protein tyrosine phosphatase, non-receptor type 11 (PTPN11) [17]. Moreover, miR-489 regulates ovarian cancer cell survival, growth and apoptosis via suppression of Akt3 [18]. miR-489 loss promotes invasion and epithelial-mesenchymal transition (EMT) events of lung cancer cells [30].…”

“…Several studies have reported that miRNAs play pivotal roles in various cellular processes including apoptosis, proliferation, motility and differentiation [11–15]. miR-489 has been found to be underexpressed in breast cancer [16], hypopharyngeal squamous cell carcinoma [17], ovarian cancer [18], lung cancer [19] and hepatocellular carcinoma (HCC) [20]. However, miR-489 is prominently upregulated in oral squamous cell carcinoma [21], clear cell renal cell carcinoma [22, 23], suggesting that the expression and role of miR-489 are variability in different cancers.…”

MicroRNAs in gynecological cancers: Small molecules with big implications

“…let-7e [258], miR-29 [259], miR-128 [260], miR-136 [261], miR-155 [262], miR-199a [263], miR-216b [264], miR-449a [265], miR-489 [266], miR-595 [267], miR-634 [268] and miR-770 [269] inversely correlate with cisplatin resistance in OC while miR-218 [270, 271] increases sensitivity to cisplatin in CC cells. miR-21 [272, 273], miR-125b [274], miR-214 [160], miR-224 [275], miR-376c [276] and miR-509 [277] induce cisplatin resistance in OC.…”