Upregulation of miR-489-3p and miR-630 inhibits oxaliplatin uptake in renal cell carcinoma by targeting OCT2

In this study, we observed that miR-489-3p and miR-630 suppress OCT2 expression by directly binding to the OCT2 3ʹ-UTR. Meanwhile, via 786-O-OCT2-miRNAs stable expression cell models, we found that miRNAs could repress the classic substrate 1-methyl-4-phenylpyridinium (MPP+), fluorogenic substrate N,N-dimethyl-4-(2-pyridin-4-ylethenyl) aniline (ASP+), and oxaliplatin uptake by OCT2 both in vitro and in xenografts. In 33 clinical samples, miR-489-3p and miR-630 were significantly upregulated in RCC, negatively correlating with the OCT2 expression level compared to that in adjacent normal tissues, using tissue microarray analysis and qPCR validation. The increased binding of c-Myc to the promoter of pri-miR-630, responsible for the upregulation of miR-630 in RCC, was further evidenced by chromatin immunoprecipitation and dual-luciferase reporter assay. Overall, this study indicated that miR-489-3p and miR-630 function as oncotherapy-obstructing microRNAs by directly targeting OCT2 in RCC.Graphical abstractMiR-489-3p, c-Myc and miR-630 mediate OCT2 downregulation in RCC cells: MiR-489-3p and miR-630 is abnormally upregulated in RCC samples and exosomes, suppressing OCT2 expression by directly binding to the OCT2 3ʹ-UTR. The increased binding of c-Myc to the promoter of pri-miR-630, contributes to the upregulation of miR-630 in RCC.
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research