Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α
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Yang Fan1,*, Hongzhao Li1,*, Xin Ma1, Yu Gao1, Xu Bao2, Qingshan Du1, Minghui Ma1, Kan Liu1, Yuanxin Yao1, Qingbo Huang1, Yu Zhang1, Xu Zhang1
1Department of Urology, State Key Laboratory of Kidney Diseases, Chinese People’s Liberation Army General Hospital, PLA Medical School, Beijing, People’s Republic of China
2Medical School, Nankai University, Tianjin, People’s Republic of China
*These authors contributed equally to this work
Xu Zhang, e-mail: firstname.lastname@example.org
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
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.
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