miR-31 Ablates Expression of the HIF Regulatory Factor FIH to Activate the HIF Pathway in Head and Neck Carcinoma
miR-31 Ablates Expression of the HIF Regulatory Factor FIH to Activate the HIF Pathway in Head and Neck Carcinoma
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DOI：
10.1158/0008-5472.can-09-2291
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Chang, Kuo-Wei
中科院分区：
文献类型：
--
作者：
Liu, Chung-Ji;Tsai, Meng-Miao;Chang, Kuo-Wei
microRNA（miRNA）是一类内源性表达的非编码RNA，具有重要的生物学和病理学功能，但其功能尚未完全阐明。这项研究调查了头颈部鳞状细胞癌（HNSCC）中miRNA表达的变化，其发病率在全球范围内不断上升。初步筛选和随后的分析确定了一组异常表达的miRNA在HNSCC组织中，其中miR-31最显着上调。在细胞培养或肿瘤异种移植物中，miR-31的异位表达在常氧条件下增加了HNSCC细胞的致癌潜力。相反，阻断miR-31表达减少了肿瘤异种移植物的生长。计算机模拟分析表明，miR-31可能靶向因子抑制低氧诱导因子（FIH）的3'非翻译区（UTR），FIH是一种低氧诱导因子（HIF）调节因子，可抑制HIF在常氧条件下作为转录调节因子的能力。为了支持这种可能性，miR-31表达抑制了FIH表达，并且FIH 3' UTR中的预测性miR-31靶位点内的突变消除了FIH抑制。此外，miR-31表达增加HIF反式激活活性。我们发现，FIH抑制致癌表型在常氧条件下，这种活性被废除的功能突变。最后，miR-31表达增加与肿瘤组织中FIH水平降低相关。我们的研究结果表明，miR-31有助于HNSCC的发展，在常氧条件下阻碍FIH激活HIF。Cancer Res; 70（4）; 1635-44. (C)2010年AACR。
MicroRNAs (miRNA) are endogenously expressed noncoding RNAs with important biological and pathological functions that are yet to be fully defined. This study investigated alterations in miRNA expression in head and neck squamous cell carcinoma (HNSCC), the incidence of which is rising throughout the world. Initial screening and subsequent analysis identified a panel of aberrantly expressed miRNAs in HNSCC tissues, with miR-31 among the most markedly upregulated. Ectopic expression of miR-31 increased the oncogenic potential of HNSCC cells under normoxic conditions in cell culture or tumor xenografts. Conversely, blocking miR-31 expression reduced the growth of tumor xenografts. The in silico analysis suggested that miR-31 may target the 3' untranslated region (UTR) of factor-inhibiting hypoxia-inducible factor (FIH), a hypoxia-inducible factor (HIF) regulatory factor that inhibits the ability of HIF to act as a transcriptional regulator under normoxic conditions. In support of this likelihood, miR-31 expression repressed FIH expression and mutations within the predictive miR-31 target site in the FIH 3' UTR abrogated FIH repression. Furthermore, miR-31 expression increased HIF transactivation activity. We found that FIH suppressed oncogenic phenotypes under normoxic conditions and that this activity was abrogated by functional mutations. Lastly, increased miR-31 expression was correlated with decreased levels of FIH in tumor tissues. Our findings suggest that miR-31 contributes to the development of HNSCC by impeding FIH to activate HIF under normoxic conditions. Cancer Res; 70(4); 1635-44. (C) 2010 AACR.