TMPRSS4 induces invasion and epithelial-mesenchymal transition through upregulation of integrin alpha5 and its signaling pathways.
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.
Kim
Semi
S
Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 305-806, Korea. semikim@kribb.re.kr
Kang
Hee Young
HY
Nam
Eun-Hee
EH
Choi
Myung-Sook
MS
Zhao
Xue-Feng
XF
Hong
Chang Soo
CS
Lee
Jung Weon
JW
Lee
Jae Hyuk
JH
Park
Young-Kyu
YK
D015820:Cadherins / Q000502:physiology; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006801:Humans; D039482:Integrin alpha5 / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness; D012697:Serine Endopeptidases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D015820:Cadherins; D039482:Integrin alpha5; D008565:Membrane Proteins; C107953:RAC1 protein, human; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human; D020830:rac1 GTP-Binding Protein