Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α.

// Yang Fan 1, * , Hongzhao Li 1, * , Xin Ma 1 , Yu Gao 1 , Xu Bao 2 , Qingshan Du 1 , Minghui Ma 1 , Kan Liu 1 , Yuanxin Yao 1 , Qingbo Huang 1 , Yu Zhang 1 , Xu Zhang 1 1 Department of Urology, State Key Laboratory of Kidney Diseases, Chinese People’s Liberation Army General Hospital, PLA Medical School, Beijing, People’s Republic of China 2 Medical School, Nankai University, Tianjin, People’s Republic of China * These authors contributed equally to this work Correspondence to: Xu Zhang, e-mail: xzhang@foxmail.com Keywords: clear cell renal cell carcinoma, von Hippel–Lindau, hypoxia-inducible factor, dicer, microRNA Received: September 08, 2015      Accepted: January 23, 2016      Published: March 01, 2016 ABSTRACT Both the von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) pathway and microRNA (miRNA) regulation are important mechanisms underlying the development and progression of clear cell renal cell carcinoma (ccRCC). Here we demonstrate that VHL deficiency leads to downregulation of Dicer and, in turn, defects in the miRNA biogenesis machinery in ccRCCs. Dicer inhibited expression of HIF-2α, which was a direct target of Dicer-dependent miR-182-5p in VHL-deficient ccRCCs. Ectopic Dicer expression in VHL-deficient ccRCCs suppressed tumor growth and angiogenesis by inhibiting HIF-2α both in vitro and in vivo . Reduced Dicer mRNA levels served as an independent prognostic factor for poor survival in patients with VHL-deficient ccRCC. Our results indicate that downregulation of Dicer in VHL-deficient ccRCCs contributes to high levels of HIF-2α and a malignant phenotype, which suggests Dicer could be a useful therapeutic target for managing this disease.