Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1
Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1
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通过靶向 N-RAS 和 IRS1 下调与癌症进展和 VEGF 转录激活相关的 miR-145
DOI：
10.1016/j.bbagrm.2012.11.006
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发表时间：
2013-02-01
影响因子：
4.7
通讯作者：
Liu, Ling-Zhi
中科院分区：
文献类型：
--
作者：
Yin, Yu;Yan, Zhi-Ping;Liu, Ling-Zhi
microRNA-145（miR-145）在各种肿瘤类型中下调。然而，其抑制肿瘤生长和血管生成的机制仍有待阐明。本研究发现miR-145在结直肠癌（CRC）患者血浆和癌组织中表达显著下调，过表达miR-145抑制细胞增殖、迁移和侵袭。为了了解miR-145抑制肿瘤生长的潜在机制，我们发现miR-145通过直接靶向N-RAS和IRS 1，阻断AKT和ERK 1/2通路的激活，以及HIF-1和VEGF的表达，而VEGF是肿瘤生长的重要效应因子。N-RAS和IRS 1的强制表达通过转录激活恢复VEGF表达。MiR-145还抑制N-RAS和IRS 1表达，从而抑制小鼠异种移植肿瘤中的AKT和ERK 1/2活化以及VEGF表达。为了检验这些结果的临床相关性，我们使用了60对结直肠癌组织和癌旁正常组织，分析了这些组织中miR-145、N-RAS和IRS 1的表达水平，发现这些结直肠癌组织中miR-145水平与N-RAS和IRS 1水平显著负相关，这表明我们的研究结果在未来的结肠直肠癌诊断和治疗的翻译应用中具有重要意义。(c)2012 Elsevier B. V.保留所有权利。
MicroRNA-145 (miR-145) is downregulated in various tumor types. However, its mechanism in inhibiting tumor growth and angiogenesis remains to be elucidated. In this study, we found that miR-145 was significantly downregulated in the plasma and cancer tumor tissues of colorectal cancer (CRC) patients, and overexpression of miR-145 inhibited cell proliferation, migration and invasion. To understand the potential mechanism of miR-145 in inhibiting tumor growth, we showed that miR-145 blocked the activation of AKT and ERK1/2 pathways, and the expression of HIF-1 and VEGF via directly targeting N-RAS and IRS1, and VEGF is an important effector for tumor growth. Forced expression of N-RAS and IRS1 restored VEGF expression via transcriptional activation. MiR-145 also inhibited N-RAS and IRS1 expression to suppress AKT and ERK1/2 activation, and VEGF expression in mouse xenograft tumors. To test the clinical relevance of these results, we used 60 pairs of colorectal cancer tissues and adjacent normal tissues, analyzed the levels of miR-145, N-RAS and IRS1 expression in these tissues, and found that miR-145 levels were significantly inversely correlated with N-RAS and IRS1 levels in these colorectal cancer tissues, suggesting the important implication of our findings in translational application for colorectal cancer diagnostics and treatment in the future. (c) 2012 Elsevier B.V. All rights reserved.