MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma
MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma
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DOI：
10.1038/onc.2008.178
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发表时间：
2008-09-01
期刊：
影响因子：
8
通讯作者：
Negrini, M.
中科院分区：
文献类型：
--
作者：
Fornari, F.;Gramantieri, L.;Negrini, M.
靶mRNA的鉴定是评估异常表达的microRNA在人类癌症中的作用的关键步骤。miR-221在人肝细胞癌（HCC）以及其他恶性肿瘤中上调。miR-221的一个已证实的靶点是CDKN 1B/p27，其下调影响HCC预后。在这里，我们证明了细胞周期蛋白依赖性激酶抑制剂（CDKI）CDKN 1C/p57也是miR-221的直接靶点。事实上，CDKN 1B/p27和CDKN 1C/p57两者的下调均响应于miR-221转染到HCC衍生细胞中而发生，并且CDKN 1B/p27和CDKN 1C/p57两者的显著上调均响应于antimiR-221转染而发生。还证实了miR-221与CDKN 1C/p57 mRNA的30个UTR上的靶位点的直接相互作用。通过控制这两种CDKI，上调miR-221可以通过增加S期细胞的数量来促进HCC细胞的生长。为了评估这些研究在原发性肿瘤中的相关性，分析了匹配的HCC和肝硬化样本的miR-221、CDKN 1B/p27和CDKN 1C/p57表达。miR-221在71%的HCC中上调，而CDKN 1B/p27和CDKN 1C/p57蛋白在77%的病例中下调。在HCC中发现miR-221与CDKN 1B/p27和CDKN 1C/p57之间存在显著负相关。总之，我们认为miR-221通过靶向CDKN 1B/p27和CDKN 1C/p57在肝癌发生中具有致癌功能，从而通过控制细胞周期抑制剂促进增殖。这些发现为开发旨在阻断HCC中miR-221的治疗策略奠定了基础。
The identification of target mRNAs is a key step for assessing the role of aberrantly expressed microRNAs in human cancer. MiR-221 is upregulated in human hepatocellular carcinoma (HCC) as well as in other malignancies. One proven target of miR-221 is CDKN1B/p27, whose downregulation affects HCC prognosis. Here, we proved that the cyclin-dependent kinase inhibitor (CDKI) CDKN1C/p57 is also a direct target of miR-221. Indeed, downregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to miR-221 transfection into HCC-derived cells and a significant upregulation of both CDKN1B/p27 and CDKN1C/p57 occurs in response to antimiR-221 transfection. A direct interaction of miR-221 with a target site on the 30 UTR of CDKN1C/p57 mRNA was also demonstrated. By controlling these two CDKIs, upregulation of miR-221 can promote growth of HCC cells by increasing the number of cells in S-phase. To assess the relevance of these studies in primary tumors, matched HCC and cirrhosis samples were assayed for miR-221, for CDKN1B/p27 and CDKN1C/p57 expression. MiR-221 was upregulated in 71% of HCCs, whereas CDKN1B/p27 and CDKN1C/p57 proteins were down-regulated in 77% of cases. A significant inverse correlation between miR-221 and both CDKN1B/p27 and CDKN1C/p57 was found in HCCs. In conclusion, we suggest that miR-221 has an oncogenic function in hepatocarcinogenesis by targeting CDKN1B/p27 and CDKN1C/p57, hence promoting proliferation by controlling cell-cycle inhibitors. These findings establish a basis toward the development of therapeutic strategies aimed at blocking miR-221 in HCC.