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

Hye-Jin Min1, Yunhee Lee2, Xue-Feng Zhao3

  • 1Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.

Cellular Signalling
|August 28, 2013
PubMed

Insights

Transmembrane serine protease TMPRSS4 (TMPRSS4) drives cancer cell invasion by upregulating urokinase-type plasminogen activator (uPA) gene expression. This TMPRSS4-uPA axis offers a potential new target for controlling cancer spread.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • TMPRSS4, a type II transmembrane serine protease, is highly expressed in various cancers, including pancreatic, thyroid, and colon.
  • Previous studies established TMPRSS4's role in mediating tumor cell invasion, migration, and metastasis.
  • The precise molecular mechanisms underlying TMPRSS4's contribution to invasion remained incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which TMPRSS4 promotes cancer cell invasion.
  • To investigate the role of urokinase-type plasminogen activator (uPA) in TMPRSS4-mediated invasion.
  • To explore the potential correlation between TMPRSS4 and uPA expression in human cancers.

Main Methods:

  • Investigated TMPRSS4's effect on uPA gene transcription.
  • Analyzed the involvement of transcription factors Sp1, Sp3, and AP-1.
  • Assessed the role of the JNK signaling pathway.
  • Examined the function of the uPA receptor in TMPRSS4 signaling.
  • Conducted immunohistochemical analysis of TMPRSS4 and uPA expression in human lung and prostate cancer tissues.

Main Results:

  • TMPRSS4 significantly induced the transcription of the urokinase-type plasminogen activator (uPA) gene.
  • This induction was mediated by the activation of transcription factors Sp1, Sp3, and AP-1, primarily via a JNK-dependent pathway.
  • uPA induction was essential for TMPRSS4-driven cancer cell invasion and associated signaling events.
  • The uPA receptor likely participates in TMPRSS4-induced signaling and uPA expression through cell surface association with TMPRSS4.
  • A significant positive correlation was observed between uPA and TMPRSS4 expression in human lung and prostate cancers.

Conclusions:

  • TMPRSS4 acts as a key regulator of uPA gene expression in cancer cells.
  • TMPRSS4-mediated upregulation of uPA is a critical mechanism contributing to cancer cell invasion.
  • The TMPRSS4-uPA pathway represents a novel therapeutic target for controlling cancer invasion and metastasis.
Keywords:
EMTERK kinaseERK1/2FAKInvasionJNKMAPKMEKSTATTMPRSS4Transcriptionc-Jun N-terminal kinaseepithelial–mesenchymal transitionextracellular signal-regulated kinase 1/2focal adhesion kinasemitogen-activated protein kinasesiRNAsignal transducer and activator of transcriptionsmall interfering RNAuPAurokinase-type plasminogen activator

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