TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin α5 and its signaling pathways
TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin α5 and its signaling pathways
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DOI：
10.1093/carcin/bgq024
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发表时间：
2010-04-01
期刊：
影响因子：
4.7
通讯作者：
Park, Young-Kyu
中科院分区：
文献类型：
--
作者：
Kim, Semi;Kang, Hee Young;Park, Young-Kyu
TMPRSS 4是一种新型的II型跨膜丝氨酸蛋白酶，在胰腺、甲状腺和其他癌组织的细胞表面高度表达，但其致癌意义和分子机制尚不清楚。以前，我们已经表明，TMPRSS 4通过促进上皮间质转化（EMT）促进人类肿瘤细胞的侵袭，迁移和转移。在这项研究中，我们探讨了TMPRSS 4介导的作用的分子基础。我们发现，多个下游信号通路，包括粘着斑激酶（FAK），细胞外信号调节激酶（ERK），Akt，Src和Rac 1，激活TMPRSS 4的表达和FAK信号和ERK激活所需的TMPRSS 4诱导的侵袭性和EMT，包括钙粘蛋白开关。抑制PI 3 K或Src降低了TMPRSS 4介导的侵袭性和肌动蛋白重排，而不恢复E-钙粘蛋白表达。下调E-钙粘蛋白是TMPRSS 4介导的效应所必需的，但不足以诱导EMT和侵袭。TMPRSS 4诱导整合素α 5的表达及其信号转导，导致侵袭性和EMT伴随着E-钙粘蛋白的下调。功能阻断证实整合素α 5 β 1是一种关键的信号分子，足以诱导TMPRSS 4介导的效应。免疫组化结果显示，TMPRSS 4在进展期大肠癌组织中的表达明显高于早期大肠癌组织。此外，TMPRSS 4的上调与整合素α 5表达的增强相关。这些观察结果表明整合素α 5上调是TMPRSS 4诱导侵袭并促进癌症进展的分子机制。
TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid and other cancer tissues, although its oncogenic significance and molecular mechanisms are unknown. Previously, we have shown that TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition (EMT). In this study, we explored the molecular basis underlying TMPRSS4-mediated effects. We show that multiple downstream signaling pathways, including focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), Akt, Src and Rac1, are activated by TMPRSS4 expression and that FAK signaling and ERK activation are required for TMPRSS4-induced invasiveness and EMT, including cadherin switch. Inhibition of PI3K or Src reduced invasiveness and actin rearrangement mediated by TMPRSS4 without restoring E-cadherin expression. Downregulation of E-cadherin was required for TMPRSS4-mediated effects but was not sufficient to induce EMT and invasion. TMPRSS4 induced integrin alpha 5 expression and its signal transduction, leading to invasiveness and EMT accompanied by downregulation of E-cadherin. Functional blocking confirmed that integrin alpha 5 beta 1 is a critical signaling molecule that is sufficient to induce TMPRSS4-mediated effects. Immunohistochemical analysis showed that TMPRSS4 expression was significantly higher in human colorectal cancer tissues from advanced stages than in that of early stage. Furthermore, upregulation of TMPRSS4 was correlated with enhanced integrin alpha 5 expression. These observations implicate integrin alpha 5 upregulation as a molecular mechanism by which TMPRSS4 induces invasion and contributes to cancer progression.