CADM1 promotes malignant features of small-cell lung cancer by recruiting 4.1R to the plasma membrane
CADM1 promotes malignant features of small-cell lung cancer by recruiting 4.1R to the plasma membrane
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DOI：
10.1016/j.bbrc.2020.11.121
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发表时间：
2021-01-01
影响因子：
3.1
通讯作者：
Murakami, Yoshinori
中科院分区：
文献类型：
--
作者：
Funaki, Toko;Ito, Takeshi;Murakami, Yoshinori
细胞黏附分子1(CADM1)在小细胞肺癌(SCLC)中高表达，并能增强SCLC细胞在裸鼠体内的致瘤性。在这里，我们研究了CADM1在小细胞肺癌中致癌作用的分子机制。CADM1促进SCLC细胞在软琼脂中的集落形成。对CADM1中保守的蛋白结合基序的缺失和点突变分析表明，胞质区域的4.1蛋白结合基序负责促进克隆形成。在与肌动蛋白结合的4.1蛋白中，4.1R是唯一一种定位于细胞膜上的蛋白，其定位依赖于SCLC细胞中CADM1的表达。4.1R的敲除抑制了CADM1促进的集落形成，提示CADM1在小细胞肺癌中的致癌作用需要4.1R。在原发的小细胞肺癌中，CADM1的表达与4.1R的膜定位有关，正如在小细胞肺癌细胞系中观察到的那样。此外，CADM1和4.1R的膜性共定位与肿瘤分期有关。这些结果提示CADM1-4.1R复合体的形成可能促进了小细胞肺癌的恶性特征。(C)2020作者。由爱思唯尔公司出版。
Cell adhesion molecule 1 (CADM1), which mediates intercellular adhesion between epithelial cells, is shown to be highly expressed in small-cell lung cancer (SCLC) and to enhance tumorigenicity of SCLC cells in nude mice. Here, we investigated the molecular mechanism underlying the oncogenic role of CADM1 in SCLC. CADM1 promoted colony formation of SCLC cells in soft agar. Analysis of deletion and point mutants of the conserved protein-binding motifs in CADM1 revealed that the 4.1 protein-binding motif in the cytoplasmic domain is responsible for the promotion of colony formation. Among the actin-binding 4.1 proteins, 4.1R was the only protein whose localization to the plasma membrane is dependent on CADM1 expression in SCLC cells. Knockdown of 4.1R suppressed the colony formation enhanced by CADM1, suggesting that 4.1R is required for the oncogenic role of CADM1 in SCLC. In primary SCLC, CADM1 expression was correlated with membranous localization of 4.1R, as was observed in a SCLC cell line. Moreover, membranous co-localization of CADM1 and 4.1R was associated with more advanced tumor stage. These results suggest that the formation of CADM1-4.1R complex would promote malignant features of SCLC. (C) 2020 The Authors. Published by Elsevier Inc.