Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.
Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), Mexico DF, Mexico.
Oncogene. 2014 Sep 4;33(36):4531-6. doi: 10.1038/onc.2013.442. Epub 2013 Oct 28.
Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.
桥粒钙黏蛋白介导上皮组织中的细胞-细胞黏附，并且已经知道在癌症中发生改变。我们之前已经表明，两种肠上皮桥粒钙黏蛋白之一，桥粒胶蛋白 2（Dsc2）的缺失会促进结肠上皮癌肿瘤细胞的增殖和肿瘤形成。在这项研究中，我们表明另一种与 Dsc2 配对的肠桥粒钙黏蛋白，桥粒芯胶蛋白 2（Dsg2）的缺失会导致上皮细胞增殖减少，并抑制小鼠的异种移植物肿瘤生长。Dsg2 缺陷细胞表现出 Dsc2 表达的代偿性增加，并且通过小干扰 RNA 介导的 Dsc2 缺失恢复了 Dsg2 缺陷细胞的增殖。Dsg2 的下调通过改变 EGFR 和下游细胞外信号调节激酶的磷酸化来抑制表皮生长因子受体（EGFR）信号和细胞增殖，同时抑制 EGFR 受体内化。此外，我们证明了 Dsc2 在控制肠上皮细胞中的 EGFR 信号和细胞增殖中起着核心作用。与这些发现一致，对人结肠癌的分析表明 Dsg2 蛋白表达增加。总之，这些数据表明，桥粒钙黏蛋白伴侣 Dsg2 和 Dsc2 通过对 EGFR 信号的不同影响在控制结肠癌细胞增殖中发挥相反的作用。
