title: Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α.
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.
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: Hongzhao
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Medical School, Nankai University, Tianjin, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Bao
authors.affiliation: 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.
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Minghui
authors.initials: M
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Kan
authors.initials: K
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D053487:DEAD-box RNA Helicases; D035683:MicroRNAs; D012333:RNA, Messenger; D043244:Ribonuclease III; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C538984:Mirn182 microRNA, human; C408087:DICER1 protein, human
keywords: clear cell renal cell carcinoma; dicer; hypoxia-inducible factor; microRNA; von Hippel-Lindau