MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer
MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer
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DOI：
10.1053/j.gastro.2007.05.022
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发表时间：
2007-08-01
期刊：
影响因子：
29.4
通讯作者：
Patel, Tushar
中科院分区：
文献类型：
--
作者：
Meng, Fanyin;Henson, Roger;Patel, Tushar
背景与目的：microRNAs（miRNAs）是一类负调控基因表达的非编码短RNA。尽管已经假设了异常miRNA表达在癌症中的作用，但是异常表达的miRNA与肿瘤生物学的病理生理作用和相关性尚未确定。研究方法：我们通过表达谱分析评估了miRNA在人肝细胞癌（HCC）中的表达，并确定了上调的miRNA的靶基因和生物学功能效应。结果：在使用miRNA微阵列的表达谱研究中，发现miR-21在HCC肿瘤和细胞系中高度过表达。在培养的HCC细胞中抑制miR-21增加了磷酸酶和张力蛋白同源物（PTEN）肿瘤抑制因子的表达，并降低了肿瘤细胞的增殖、迁移和侵袭。相反，通过转染前体miR-21增强miR-21表达增加了肿瘤细胞增殖、迁移和侵袭。此外，在用前体miR-21转染的正常人肝细胞中观察到细胞迁移增加。PTEN被证明是miR-21的直接靶点，并且有助于miR-21对细胞侵袭的作用。miR-21的调节改变了粘着斑激酶磷酸化和基质金属蛋白酶2和9的表达，这两种蛋白酶都是参与细胞迁移和侵袭的PTEN下游介质。结论：miR-21的异常表达可以通过调节PTEN表达和参与介导癌细胞表型特征（如细胞生长、迁移和侵袭）的PTEN依赖性途径来促进HCC的生长和扩散。
Background & Aims: microRNAs (miRNAs) are short noncoding RNAs that regulate gene expression negatively. Although a role for aberrant miRNA expression in cancer has been postulated, the pathophysiologic role and relevance of aberrantly expressed miRNA to tumor biology has not been established. Methods: We evaluated the expression of miRNA in human hepatocellular cancer (HCC) by expression profiling, and defined a target gene and biologically functional effect of an up-regulated miRNA. Results: miR-21 was noted to be highly overexpressed in HCC tumors and cell lines in expression profiling studies using a miRNA microarray. Inhibition of miR-21 in cultured HCC cells increased expression of the phosphatase and tensin homolog (PTEN) tumor suppressor, and decreased tumor cell proliferation, migration, and invasion. In contrast-enhanced miR-21 expression by transfection with precursor miR-21 increased tumor cell proliferation, migration, and invasion. Moreover, an increase in cell migration was observed in normal human hepatocytes transfected with precursor miR-21. PTEN was shown to be a direct target of miR-21, and to contribute to miR-21 effects on cell invasion. Modulation of miR-21 altered focal adhesion kinase phosphorylation and expression of matrix metalloproteases 2 and 9, both downstream mediators of PTEN involved in cell migration and invasion. Conclusions: Aberrant expression of miR-21 can contribute to HCC growth and spread by modulating PTEN expression and PTEN-dependent pathways involved in mediating phenotypic characteristics of cancer cells such as cell growth, migration, and invasion.