TMPRSS4 upregulates uPA gene expression through JNK signaling activation to induce cancer cell invasion

Abstract

TMPRSS4 is a novel type II transmembrane serine protease that is highly expressed in pancreatic, thyroid, colon, and other cancer tissues. Previously, we demonstrated that TMPRSS4 mediates tumor cell invasion, migration, and metastasis. However, the mechanisms by which TMPRSS4 contributes to invasion are not fully understood. Here, we demonstrated that TMPRSS4 induced the transcription of the urokinase-type plasminogen activator (uPA) gene through activating the transcription factors Sp1, Sp3, and AP-1 in mainly a JNK-dependent manner and that the induction of uPA was required for TMPRSS4-mediated cancer cell invasion and signaling events. In addition, the uPA receptor was involved in TMPRSS4-induced signaling activation and subsequent uPA expression probably through its association with TMPRSS4 on the cell surface. Immunohistochemical analysis showed that uPA expression was significantly correlated with TMPRSS4 expression in human lung and prostate cancers. These observations suggest that TMPRSS4 is an important regulator of uPA gene expression; the upregulation of uPA by TMPRSS4 contributes to invasion and may represent a novel mechanism for the control of invasion.