Replisome genes regulation by anti-tumor miR-101-5p in clear cell renal cell carcinoma.

Analysis of microRNA (miRNA) regulatory networks is useful for exploring novel biomarkers and therapeutic targets in cancer cells. The Cancer Genome Atlas (TCGA) dataset shows that low expression of both strands of pre-miR-101 (miR-101-5p and miR-101-3p) significantly predicted poor prognosis in clear cell renal cell carcinoma (ccRCC). The functional significance of miR-101-5p in cancer cells is poorly understood. Here, we focused on miR-101-5p to investigate the anti-tumor function and its regulatory networks in ccRCC cells. Ectopic expression of mature miRNAs or siRNAs was investigated in cancer cell lines to characterize cell function, i.e., proliferation, apoptosis, migration and invasion. Genome-wide gene expression and in silico database analyses were performed to predict miRNA regulatory networks. Expression of miR-101-5p caused cell cycle arrest and apoptosis in ccRCC cells. Downstream neighbor of son (DONSON) was directly regulated by miR-101-5p, and its aberrant expression was significantly associated with shorter survival in propensity score-matched analysis (P = 0.0001). Knockdown of DONSON attenuated ccRCC cell aggressiveness. Several replisome genes controlled by DONSON and their expression were closely associated with ccRCC pathogenesis. The anti-tumor miR-101-5p/DONSON axis and its modulated replisome genes might be a novel diagnostic and therapeutic target for ccRCC.

Cancer science. 2020 Jan 23 [Epub ahead of print]

Yasutaka Yamada, Nijiro Nohata, Akifumi Uchida, Mayuko Kato, Takayuki Arai, Shogo Moriya, Keiko Mizuno, Satoko Kojima, Kazuto Yamazaki, Yukio Naya, Tomohiko Ichikawa, Naohiko Seki

Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba, Japan., MSD K.K, Tokyo, Japan., Department of Pulmonary Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan., Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chiba, Japan., Department of Urology, Teikyo University Chiba Medical Center, Ichihara, Japan., Department of Pathology, Teikyo University Chiba Medical Center, Ichihara, Japan., Department of Urology, Chiba University Graduate School of Medicine, Chiba, Japan.