Quantitatively Controlling Expression of miR-17∼92 Determines Colon Tumor Progression in a Mouse Tumor Model
Quantitatively Controlling Expression of miR-17∼92 Determines Colon Tumor Progression in a Mouse Tumor Model
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DOI：
10.1016/j.ajpath.2014.01.037
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发表时间：
2014-05-01
影响因子：
6
通讯作者：
Zhang, Huang-Ge
中科院分区：
文献类型：
--
作者：
Jiang, Hong;Wang, Ping;Zhang, Huang-Ge
miRNA簇miR-17与92相似，靶向参与促进或抑制肿瘤进展的不同途径的mRNA。然而，miR-17类似于92簇介导的促肿瘤发生或抗肿瘤发生作用的细胞和分子机制尚未研究。在此，我们确定结肠癌进展的抑制通过定量控制类似于92簇的miR-17的表达来决定。miR-19与miR-17相似，中等水平的miR-17通过靶向抑癌基因PTEN诱导Wnt/β-catenin介导的上皮间质转化促进肿瘤转移。然而，类似于92簇的较高水平的miR-17通过miR-18 a从PTEN转换到癌基因，包括Ctnnb 1（β-连环蛋白），这导致肿瘤生长和转移的抑制。然而，在具有类似于92的高水平miR-17的肿瘤细胞中，Ctnnb 1的过表达并没有导致β-catenin蛋白水平的增加，这表明类似于92的高水平miR-17调节的其他因素也可能有助于抑制肿瘤生长和转移。这些未知因素可能对β-catenin蛋白的产生有负调控作用。总的来说，本研究中提供的数据显示，类似于92的较高水平的miR-17是激活Wnt/β-连环蛋白途径的关键负调节因子，并且可能具有潜在的治疗应用。
The miRNA duster miR-17 similar to 92 targets mRNAs involved in distinct pathways that either promote or inhibit tumor progression. However, the cellular and molecular mechanisms underlying miR-17 similar to 92 cluster-mediated protumorigenic or anti-tumorigenic effects have not been studied. Herein, we determined that inhibition of colon cancer progression is dictated by quantitatively controlling expression of the miR-17 similar to 92 cluster. miR-19 in the context of the miR-17 similar to 92 cluster at medium Levels promoted tumor metastasis through induction of Wnt/beta-catenin mediated epithelialmesenchymal transition by targeting to the tumor-suppressor gene, PTEN. However, higher Levels of the miR-17 similar to 92 cluster switched from PTEN to oncogenes, including Ctnnb1 (beta-catenin) via miR-18a, which resulted in inhibition of tumor growth and metastasis. However, overexpression of Ctnnb1in tumor cells with high-level miR-17 similar to 92 did not lead to an increase in the Levels of beta-catenin protein, suggesting that other factors regulated by higher Levels of miR-17 similar to 92 might also contribute to inhibition of tumor growth and metastasis. Those unidentified factors may negatively regulate the production of beta-catenin protein. Collectively, the data presented in this study revealed that higher Levels of miR-17 similar to 92 were a critical negative regulator for activation of the Wnt/beta-catenin pathway and could have a potential therapeutic application.