Ramsay Alan G, Keppler Melanie D, Jazayeri Mona, Thomas Gareth J, Parsons Maddy, Violette Shelia, Weinreb Paul, Hart Ian R, Marshall John F
Centre for Tumour Biology, Institute of Cancer and Cancer Research UK Clinical Centre, London, United Kingdom.
Cancer Res. 2007 Jun 1;67(11):5275-84. doi: 10.1158/0008-5472.CAN-07-0318.
Enhanced expression levels of integrin alphavbeta6 have been linked to more aggressive invasive carcinoma cell behavior and poorer clinical prognosis. However, how alphavbeta6 determines invasion and the dynamics of integrin alphavbeta6 regulation in tumor cells are poorly understood. We have identified the 35-kDa HS1-associated protein X-1 (HAX-1) protein as a novel binding partner of the beta6 cytoplasmic tail using a yeast two-hybrid screen. We show that alphavbeta6-dependent migration is blocked following small interfering RNA (siRNA)-mediated depletion of HAX-1 in oral squamous cell carcinoma cell lines. Using both siRNA and membrane-permeable peptides, we show that alphavbeta6-dependent migration and invasion require HAX-1 to bind directly to beta6 and thereby regulate clathrin-mediated endocytosis of alphavbeta6 integrins. Progression of oral cancer is associated with enhanced expression of alphavbeta6 and HAX-1 proteins in patient tissue. This report establishes that integrin endocytosis is required for alphavbeta6-dependent carcinoma cell motility and invasion and suggests that this process is an important mechanism in cancer progression.
整合素αvβ6表达水平的升高与侵袭性更强的癌细胞行为及更差的临床预后相关。然而，αvβ6如何决定侵袭以及肿瘤细胞中整合素αvβ6调控的动力学仍知之甚少。我们通过酵母双杂交筛选，鉴定出35 kDa的HS1相关蛋白X-1（HAX-1）蛋白是β6细胞质尾巴的新型结合伴侣。我们发现，在口腔鳞状细胞癌细胞系中，小干扰RNA（siRNA）介导的HAX-1缺失会阻断αvβ6依赖性迁移。使用siRNA和膜通透性肽，我们表明αvβ6依赖性迁移和侵袭需要HAX-1直接结合β6，从而调节网格蛋白介导的αvβ6整合素内吞作用。口腔癌的进展与患者组织中αvβ6和HAX-1蛋白表达的增强有关。本报告证实整合素内吞作用是αvβ6依赖性癌细胞运动和侵袭所必需的，并表明该过程是癌症进展中的重要机制。
