Mitra Aparna, Chakrabarti Jayati, Chatterjee Amitava
Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute Kolkata, India.
J Environ Pathol Toxicol Oncol. 2003;22(3):167-78. doi: 10.1615/jenvpathtoxoncol.v22.i3.20.
The integrin multigene family, comprising at least 21 distinct heterodimeric complexes, includes receptors for all major extracellular proteins such as fibronectin, laminin, vitronectin, and collagens. These receptors play important roles in various physiological processes. Matrixmetallo-proteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade the extracellular matrix (ECM) components in physiological conditions. MMPs can degrade all structural components of the ECM, which is one of the critical aspects of tumor cell invasion. The role of matrilysin (MMP-7) in the progression of various carcinomas was recently addressed. Evidence of interplay between integrin function and ECM matrix integrity has come from experiments showing that integrin-ECM contacts can regulate expression and function of MMPs. In this communication, we report on an interesting interrelationship between cell surface alpha5beta1 integrin (fibronectin receptor) and MMPs (MMP-2 and MMP-7).
The zymographic analysis showed that ligation of cell surface alpha5beta1 integrin by alpha5 monoclonal antibody leads to the expression and activation of MMP-2 and MMP-7 in B16F10 melanoma cells. The immunoblot confirmed the tyrosine phosphorylation of FAK in B16F10 cells grown in presence of alpha5 monoclonal antibody, indicating the transduction of signal via FAK. The immunocytochemical study demonstrated that alpha5beta1 integrin stimulation causes rearrangement of actin fibers and its accumulation in focal adhesion sites.
alpha5beta1 integrin-induced expression and activation of MMP-2 and -7 indicates the role of tumor cell surface integrin receptor in the modulation of MMPs and, thereby, the invasive property of tumor cells.
整合素多基因家族由至少21种不同的异二聚体复合物组成，包括所有主要细胞外蛋白的受体，如纤连蛋白、层粘连蛋白、玻连蛋白和胶原蛋白。这些受体在各种生理过程中发挥重要作用。基质金属蛋白酶（MMPs）是一类锌依赖性内肽酶，在生理条件下可降解细胞外基质（ECM）成分。MMPs能降解ECM的所有结构成分，这是肿瘤细胞侵袭的关键环节之一。最近研究了基质溶素（MMP - 7）在各种癌症进展中的作用。整合素功能与ECM基质完整性之间相互作用的证据来自实验，这些实验表明整合素与ECM的接触可调节MMPs的表达和功能。在本通讯中，我们报告了细胞表面α5β1整合素（纤连蛋白受体）与MMPs（MMP - 2和MMP - 7）之间有趣的相互关系。
酶谱分析表明，α5单克隆抗体与细胞表面α5β1整合素结合可导致B16F10黑色素瘤细胞中MMP - 2和MMP - 7的表达和激活。免疫印迹证实了在α5单克隆抗体存在下生长的B16F10细胞中FAK的酪氨酸磷酸化，表明信号通过FAK转导。免疫细胞化学研究表明，α5β1整合素刺激导致肌动蛋白纤维重排并在粘着斑部位积累。
α5β1整合素诱导的MMP - 2和 - 7的表达和激活表明肿瘤细胞表面整合素受体在调节MMPs以及肿瘤细胞侵袭特性中的作用。
