MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin.
MicroRNA-26a promotes cholangiocarcinoma growth by activating β-catenin.
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MicroRNA-26A通过激活β-catenin促进胆管癌的生长。
DOI：
10.1053/j.gastro.2012.03.045
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发表时间：
2012-07
期刊：
影响因子：
29.4
通讯作者：
Wu T
中科院分区：
文献类型：
--
作者：
Zhang J;Han C;Wu T
MicroRNAs(MiRNAs)与人类癌症的发生发展密切相关。我们研究了miR-26a在人胆管癌细胞中的作用和机制。应用原位杂交和定量逆转录聚合酶链式反应检测miR-26a在人胆管癌细胞系(如CCLP1、SG231、HuCCT1、TFK1)中的表达。用表达miR-26a1的慢病毒或干扰序列(对照)转导人胆管癌细胞系，分析其增殖和集落形成情况。我们分析了在严重联合免疫缺陷小鼠中过表达miR-26a或其抑制物的人胆管癌细胞的生长情况。免疫印迹法、免疫沉淀法、下拉法、免疫荧光法和荧光素酶报告法检测糖原合成酶-3、β，β-连环蛋白及其相关信号分子的表达和活性。人胆管癌组织和细胞系中miR-26a的表达水平高于非癌胆管上皮细胞。MiR-26a的过表达促进了胆管癌细胞的体外增殖和集落形成，而miR-26的缺失则降低了这些参数。在严重的联合免疫缺陷小鼠中，胆管癌细胞过表达miR-26a会增加肿瘤的生长，而miR-26a抑制剂的过表达会降低肿瘤的生长。通过计算分析和实验分析，确定GSK-3β信使RNA是miR-26a的直接靶标。MIR-26a介导的GSK-3β的下调导致β-连环蛋白的激活，并诱导了c-Myc、细胞周期蛋白D1和过氧化物酶体增殖物激活受体δ等下游基因的表达。缺失β-连环蛋白可部分抑制MiR-26a诱导的肿瘤细胞增殖和集落形成。MIR-26a通过抑制GSK-3β和随后激活β-连环蛋白来促进胆管癌细胞的生长。这些信号分子可能是预防或治疗胆管癌的靶点。
MicroRNAs (miRNAs) have been implicated in the development and progression of human cancers. We investigated the roles and mechanisms of miR-26a in human cholangiocarcinoma. We used in situ hybridization and quantitative reverse transcriptase polymerase chain reaction to measure expression of miR-26a in human cholangiocarcinoma tissues and cell lines (eg, CCLP1, SG231, HuCCT1, TFK1). Human cholangiocarcinoma cell lines were transduced with lentiviruses that expressed miR-26a1 or a scrambled sequence (control); proliferation and colony formation were analyzed. We analyzed growth of human cholangiocarcinoma cells that overexpress miR-26a or its inhibitor in severe combined immune-deficient mice. Immunoblot, immunoprecipitation, DNA pull-down, immunofluorescence, and luciferase reporter assays were used to measure expression and activity of glycogen synthase kinase (GSK)-3β, β-catenin, and related signaling molecules. Human cholangiocarcinoma tissues and cell lines had increased levels of miR-26a compared with the noncancerous biliary epithelial cells. Overexpression of miR-26a increased proliferation of cholangiocarcinoma cells and colony formation in vitro, whereas miR-26 depletion reduced these parameters. In severe combined immune-deficient mice, overexpression of miR-26a by cholangiocarcinoma cells increased tumor growth and overexpression of the miR-26a inhibitor reduced it. GSK-3β messenger RNA was identified as a direct target of miR-26a by computational analysis and experimental assays. miR-26a–mediated reduction of GSK-3β resulted in activation of β-catenin and induction of several downstream genes including c-Myc, cyclinD1, and peroxisome proliferator-activated receptor δ. Depletion of β-catenin partially prevented miR-26a-induced tumor cell proliferation and colony formation. miR-26a promotes cholangiocarcinoma growth by inhibition of GSK-3β and subsequent activation of β-catenin. These signaling molecules might be targets for prevention or treatment of cholangiocarcinoma.
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