Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α.
Dicer suppresses the malignant phenotype in VHL-deficient clear cell renal cell carcinoma by inhibiting HIF-2α.
复制标题
Dicer 通过抑制 HIF-2α 来抑制 VHL 缺陷的透明细胞肾细胞癌的恶性表型。
DOI：
10.18632/oncotarget.7807
复制
发表时间：
2016-04-05
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Fan Y;Li H;Ma X;Gao Y;Bao X;Du Q;Ma M;Liu K;Yao Y;Huang Q;Zhang Y;Zhang X
von Hippel-Lindau（VHL）/低氧诱导因子（HIF）通路和microRNA（miRNA）调控是肾透明细胞癌（ccRCC）发生和发展的重要机制。在这里，我们证明VHL缺陷导致Dicer下调，进而导致ccRCC中miRNA生物合成机制的缺陷。Dicer抑制HIF-2α的表达，HIF-2 α是VHL缺陷型ccRCC中Dicer依赖性miR-182- 5 p的直接靶点。VHL缺陷型ccRCC中的异位Dicer表达通过在体外和体内抑制HIF-2α来抑制肿瘤生长和血管生成。Dicer mRNA水平降低是VHL缺陷型ccRCC患者生存不良的独立预后因素。我们的研究结果表明，VHL缺陷型ccRCC中Dicer的下调导致高水平的HIF-2α和恶性表型，这表明Dicer可能是管理这种疾病的有用治疗靶点。
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.