Abstract
Abstract The invasive nature of tumor cells is critical for cancer metastasis. Urokinase-type plasminogen activator (uPA), which is usually derived from stromal cells, is a well-known serine protease involved in invasion and metastasis. uPA is produced as an inactive single-chain protein (known as pro-uPA or sc-uPA) that is processed into the active disulfide-linked two-chain form of uPA by a proteolytic event. TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed on the cell surface in pancreatic, thyroid, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates colorectal tumor cell invasion, migration, and metastasis and increased TMPRSS4 expression is associated with colorectal cancer progression. We also demonstrated that TMPRSS4 upregulates uPA gene expression through c-Jun N-terminal kinase signaling activation to induce cancer cell invasion. However, it remains unknown how proteolytic activity of TMPRSS4 contributes to invasion. Here, we report that TMPRSS4 directly converted inactive pro-uPA into the active form through its proteolytic activity. Analysis of conditioned medium from cells overexpressing TMPRSS4 demonstrated that the active TMPRSS4 protease domain is released from the cells and is associated with the plasma membrane. Furthermore, TMPRSS4 could increase pro-uPA-mediated invasion in a serine proteolytic activity-dependent manner. These observations suggest that TMPRSS4 is an upstream regulator of invasion through the regulation of uPA. This study provides valuable insights into the proteolytic function of TMPRSS4 as well as mechanisms for the control of invasion. Citation Format: Hye-Jin Min, Semi Kim. TMPRSS4 proteolytically activates pro-uPA to induce cancer cell invasion. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A71. doi:10.1158/1538-7445.CHTME14-A71
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