Sechler Marybeth, Borowicz Stanley, Van Scoyk Michelle, Avasarala Sreedevi, Zerayesus Sereke, Edwards Michael G, Kumar Karuppusamy Rathinam Manoj, Zhao Xiangmin, Wu Pei-Ying, Tang Ke, Bikkavilli Rama Kamesh, Winn Robert A
Cancer Biology Program, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045.
Division of Hematology and Oncology, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612.
J Biol Chem. 2015 Jun 19;290(25):15610-15620. doi: 10.1074/jbc.M114.631820. Epub 2015 Apr 29.
γ-Catenin (Plakoglobin), a well-described structural protein functioning at the adherens junctions and desmosomes, was shown to be either lost or weakly expressed in non-small cell lung cancer (NSCLC) cells and tumor tissues. However, the tumor suppressive affects of γ-catenin were not fully understood. In this study, we have identified a novel role for the affects of γ-catenin on non-small cell lung cancer (NSCLC) cell migration. Expression of γ-catenin in NSCLC cells resulted in reduced cell migration as determined by both scratch assays and trans-well cell migration assays. Moreover, the affects of γ-catenin on cell migration were observed to be p53-dependent. Mechanistically, the anti-migratory effects seen via γ-catenin were driven by the expression of hepatocyte growth factor activator inhibitor Type I (HAI-1 or SPINT-1), an upstream inhibitor of the c-MET signaling pathway. Furthermore, the re-expression of γ-catenin sensitized NSCLC cells to c-MET inhibitor-mediated growth inhibition. Taken together, we identify γ-catenin as a novel regulator of HAI-1, which is a critical regulator of HGF/c-MET signaling. Therefore, targeting γ-catenin-mediated HAI-1 expression might be a useful strategy to sensitize NSCLC to c-MET inhibitors.
γ-连环蛋白（桥粒斑珠蛋白）是一种在黏着连接和桥粒中发挥作用的结构蛋白，已有充分描述。研究表明，它在非小细胞肺癌（NSCLC）细胞和肿瘤组织中缺失或表达较弱。然而，γ-连环蛋白的肿瘤抑制作用尚未完全明确。在本研究中，我们确定了γ-连环蛋白对非小细胞肺癌（NSCLC）细胞迁移作用的新机制。通过划痕实验和Transwell细胞迁移实验测定，NSCLC细胞中γ-连环蛋白的表达导致细胞迁移减少。此外还观察到，γ-连环蛋白对细胞迁移的影响依赖于p53。从机制上讲，γ-连环蛋白介导的抗迁移作用是由肝细胞生长因子激活剂抑制剂I型（HAI-1或SPINT-1）的表达驱动的，HAI-1是c-MET信号通路的上游抑制剂。此外，γ-连环蛋白的重新表达使NSCLC细胞对c-MET抑制剂介导的生长抑制敏感。综上所述，我们确定γ-连环蛋白是HAI-1的新型调节因子，而HAI-1是HGF/c-MET信号通路的关键调节因子。因此，靶向γ-连环蛋白介导的HAI-1表达可能是使NSCLC对c-MET抑制剂敏感的有效策略。
