Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Apr;1870(4):167124. doi: 10.1016/j.bbadis.2024.167124. Epub 2024 Mar 18.
Metastasis promotes the development of tumors and is a significant cause of gastric cancer death. For metastasis to proceed, tumor cells must become mobile by modulating their cytoskeleton. MICAL1 (Molecule Interacting with CasL1) is known as an actin cytoskeleton regulator, but the mechanisms by which it drives gastric cancer cell migration are still unclear. Analysis of gastric cancer tissues revealed that MICAL1 expression is dramatically upregulated in stomach adenocarcinoma (STAD) samples as compared to noncancerous stomach tissues. Patients with high MICAL1 expression had shorter overall survival (OS), post-progression survival (PPS) and first-progression survival (FPS) compared with patients with low MICAL1 expression. RNAi-mediated silencing of MICAL1 inhibited the expression of Vimentin, a protein involved in epithelial-mesenchymal transition. This effect correlates with a significant reduction in gastric cancer cell migration. MICAL1 overexpression reversed these preventive effects. Immunoprecipitation experiments and immunofluorescence assays revealed that PlexinA1 forms a complex with MICAL1. Importantly, specific inhibition of PlexinA1 blocked the Rac1 activation and ROS production, which, in turn, impaired MICAL1 protein stability by accelerating MICAL1 ubiquitin/proteasome-dependent degradation. Overexpression of PlexinA1 enhanced Rac1 activation, ROS production, MICAL1 and Vimentin expressions, and favored cell migration. In conclusion, this study identified MICAL1 as an important facilitator of gastric cancer cell migration, at least in part, by affecting Vimentin expression and PlexinA1 promotes gastric cancer cell migration by binding to and suppressing MICAL1 degradation in a Rac1/ROS-dependent manner.
转移促进肿瘤的发展，是胃癌死亡的重要原因。为了使转移进行，肿瘤细胞必须通过调节细胞骨架变得移动。MICAL1（与 CasL1 相互作用的分子）被认为是一种肌动蛋白细胞骨架调节剂，但它驱动胃癌细胞迁移的机制尚不清楚。对胃癌组织的分析表明，与非癌性胃组织相比，MICAL1 在胃腺癌（STAD）样本中的表达显著上调。与 MICAL1 低表达的患者相比，MICAL1 高表达的患者总生存期（OS）、进展后生存期（PPS）和首次进展生存期（FPS）更短。RNAi 介导的 MICAL1 沉默抑制了上皮间质转化中涉及的蛋白波形蛋白的表达。这种效应与胃癌细胞迁移的显著减少相关。MICAL1 的过表达逆转了这些预防作用。免疫沉淀实验和免疫荧光分析表明，PlexinA1 与 MICAL1 形成复合物。重要的是，PlexinA1 的特异性抑制阻断了 Rac1 的激活和 ROS 的产生，这反过来又通过加速 MICAL1 泛素/蛋白酶体依赖性降解来损害 MICAL1 蛋白稳定性。PlexinA1 的过表达增强了 Rac1 的激活、ROS 的产生、MICAL1 和波形蛋白的表达，并有利于细胞迁移。总之，本研究确定 MICAL1 是胃癌细胞迁移的重要促进剂，至少部分是通过影响波形蛋白的表达，而 PlexinA1 通过与 MICAL1 结合并抑制 Rac1/ROS 依赖性的 MICAL1 降解来促进胃癌细胞迁移。
