Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-806, Korea.
Carcinogenesis. 2010 Apr;31(4):597-606. doi: 10.1093/carcin/bgq024. Epub 2010 Jan 29.
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 alpha5 expression and its signal transduction, leading to invasiveness and EMT accompanied by downregulation of E-cadherin. Functional blocking confirmed that integrin alpha5beta1 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 alpha5 expression. These observations implicate integrin alpha5 upregulation as a molecular mechanism by which TMPRSS4 induces invasion and contributes to cancer progression.
TMPRSS4 是一种新型的 II 型跨膜丝氨酸蛋白酶，在胰腺、甲状腺和其他癌症组织的细胞表面高度表达，尽管其致癌意义和分子机制尚不清楚。先前，我们已经表明，TMPRSS4 通过促进上皮-间充质转化（EMT）促进人肿瘤细胞的侵袭、迁移和转移。在这项研究中，我们探讨了 TMPRSS4 介导作用的分子基础。我们表明，包括粘着斑激酶（FAK）、细胞外信号调节激酶（ERK）、Akt、Src 和 Rac1 在内的多个下游信号通路被 TMPRSS4 表达激活，并且 FAK 信号和 ERK 激活是 TMPRSS4 诱导的侵袭性和 EMT 所必需的，包括钙粘蛋白开关。PI3K 或 Src 的抑制作用降低了 TMPRSS4 介导的侵袭性和肌动蛋白重排，而没有恢复 E-钙粘蛋白的表达。E-钙粘蛋白的下调是 TMPRSS4 介导作用所必需的，但不足以诱导 EMT 和侵袭。TMPRSS4 诱导整合素 alpha5 的表达及其信号转导，导致侵袭性和 EMT，并伴有 E-钙粘蛋白的下调。功能阻断证实整合素 alpha5beta1 是一种关键的信号分子，足以诱导 TMPRSS4 介导的作用。免疫组织化学分析表明，TMPRSS4 在晚期人结直肠癌组织中的表达明显高于早期。此外，TMPRSS4 的上调与整合素 alpha5 表达的增强相关。这些观察结果表明，整合素 alpha5 的上调是 TMPRSS4 诱导侵袭的分子机制，并有助于癌症进展。
