TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin  5 and its signaling pathways

Abstract

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.

Signalling pathways involved in endocrine resistance in breast cancer and associations with epithelial to mesenchymal transition (Review)

“…Consistent with the function of E-cadherin as a breast cancer invasion suppressor, experimental knockdown of E-cadherin is sufficient to confer metastatic ability (174). Conversely, exogenous E-cadherin inhibits the migration and extracellular matrix (ECM) invasion of metastatic breast cancer cells, although E-cadherin expression by itself is insufficient to completely reverse the mesenchymal phenotype (177)(178)(179). The consequences of E-cadherin loss for EMT are far reaching and reflect its dual roles in cell adhesion and signalling.…”

Inhibitory effect of soluble EP2 receptor on ovarian tumor growth in nude mice and utility of TMPRSS4 as a combinatorial molecular target

“…This indicates that some prostanoids derived from COXs suppress ovarian tumor growth and that specific inhibition of EP receptor-mediated cell signaling is a valid therapeutic strategy for peritoneal metastasis of ovarian cancer. TMPRSS4 promotes tumor growth, invasion, metastasis, and epithelialmesenchymal transition (15,34). Considering the function of TMPRSS4 in cancer cells, our data showing inhibition of cancer cell growth in SKOV/ip-FuEP2/Ex2-based peritoneal metastasis model are reasonable, and the ineffectiveness of AEBSF alone or in combination with meloxicam may be a result of the expression level of TMPRSS4 being insufficient to suppress cancer cell growth.…”

“…Setting the cut-off value of fold change as >4.0 and <0.25, respectively, revealed 6 upregulated genes and 8 downregulated genes in the SKOV/ ip-FuEP2/Ex2-derived tumor (Table II). Three upregulated genes encoded enzymes, namely MMP-7 (4.471-fold), TMPRSS4 (4.348-fold) and CYP1B1 (4.000-fold), each of which has previously been shown to be overexpressed in several types of cancer (12)(13)(14)(15)(16). To validate the result of cDNA microarray, MMP-7, TMPRSS4 and CYP1B1 mRNA from tumor tissue was detected by RT-PCR.…”

Prognostic significance of TMPRSS4 in gastric cancer

“…Jung and colleagues showed that TMPRSS4 promoted invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition [14]. Subsequebt data show that TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin alpha5 and its signaling pathways [15]. Recent studies indicate that overexpression of TMPRSS4 is significantly associated with reduced overall survival of patients with non-small cell lung cancer and breast cancer and may represent a potential therapeutic target [10][11]16].…”