Deoxycholic acid activates β-catenin signaling pathway and increases colon cell cancer growth and invasiveness
Deoxycholic acid activates β-catenin signaling pathway and increases colon cell cancer growth and invasiveness
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DOI：
10.1091/mbc.e03-12-0894
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发表时间：
2004-05-01
影响因子：
3.3
通讯作者：
Tran, T
中科院分区：
文献类型：
--
作者：
Pai, R;Tarnawski, AS;Tran, T
当发生侵袭和/或转移时，结直肠癌通常是致命的。肿瘤进展为转移表型主要取决于肿瘤细胞的侵袭性。二级胆汁酸，特别是脱氧胆酸（DCA），涉及促进结肠癌的生长和进展。DCA是否调节β-连环蛋白并促进结肠癌细胞的生长和侵袭仍然未知。由于β-连环蛋白及其靶基因尿激酶型纤溶酶原激活物受体（WAR）和细胞周期蛋白D1在结肠癌中过表达，并与癌症生长、侵袭和转移有关，我们研究了DCA是否激活β-连环蛋白信号传导并促进结肠癌细胞生长和侵袭。我们的研究结果表明，低浓度的DCA（5和50 μ M）显着增加β-连环蛋白的酪氨酸磷酸化，诱导尿激酶型纤溶酶原激活剂，uPAR和细胞周期蛋白D1的表达，并增强结肠癌细胞的增殖和侵袭。这些事件与E-钙粘蛋白与β-连环蛋白结合的大量丧失有关。用小干扰RNA抑制β-连环蛋白可显著降低DCA诱导的uPAR和细胞周期蛋白D1的表达。用中和抗体阻断uPAR可显著抑制DCA诱导的结肠癌细胞增殖和侵袭。这些发现为二级胆汁酸致癌作用的新机制提供了证据。
Colorectal cancer is often lethal when invasion and/or metastasis occur. Tumor progression to the metastatic phenotype is mainly dependent on tumor cell invasiveness. Secondary bile acids, particularly deoxycholic acid (DCA), are implicated in promoting colon cancer growth and progression. Whether DCA modulates beta-catenin and promotes colon cancer cell growth and invasiveness remains unknown. Because beta-catenin and its target genes urokinase-type plasminogen activator receptor WAR) and cyclin D1 are overexpressed in colon cancers, and are linked to cancer growth, invasion, and metastasis, we investigated whether DCA activates beta-catenin signaling and promotes colon cancer cell growth and invasiveness. Our results show that low concentrations of DCA (5 and 50 muM) significantly increase tyrosine phosphorylation of beta-catenin, induce urokinase-type plasminogen activator, uPAR, and cyclin D1 expression and enhance colon cancer cell proliferation and invasiveness. These events are associated with a substantial loss of E-cadherin binding to beta-catenin. Inhibition of beta-catenin with small interfering RNA significantly reduced DCA-induced uPAR and cyclin D1 expression. Blocking uPAR with a neutralizing antibody significantly suppressed DCA-induced colon cancer cell proliferation and invasiveness. These findings provide evidence for a novel mechanism underlying the oncogenic effects of secondary bile acids.