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Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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TRAF4 Inhibits Bladder Cancer Progression by Promoting BMP/SMAD Signaling

Prasanna Vasudevan Iyengar1,2, Dieuwke Louise Marvin1,2, Dilraj Lama3,4

  • 1Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.

Molecular Cancer Research : MCR
|June 22, 2022
PubMed

Insights

Low expression of tumor necrosis factor receptor-associated factor 4 (TRAF4) correlates with poor bladder cancer survival. TRAF4 regulates cell invasion by modulating epithelial-to-mesenchymal transition (EMT) and signaling pathways, offering a potential therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Bladder cancer is characterized by high invasiveness and metastatic potential, often leading to poor patient prognosis.
  • Epithelial-to-mesenchymal transition (EMT) is a key driver of bladder cancer invasion and metastasis.
  • The E3 ubiquitin ligase tumor necrosis factor receptor-associated factor 4 (TRAF4) is implicated as a tumor promoter in various cancers.

Purpose of the Study:

  • To investigate the role of TRAF4 in bladder cancer progression and its association with patient survival.
  • To elucidate the mechanisms by which TRAF4 influences bladder cancer cell invasion and metastasis.

Main Methods:

  • Analysis of TRAF4 expression in bladder cancer patients and cell lines.
  • Investigation of TRAF4 epigenetic regulation and post-translational modification (e.g., phosphorylation by ERK).
  • Functional studies manipulating TRAF4 expression to assess its impact on EMT markers, cell invasion, and signaling pathways (BMP/SMAD, NF-κB).
  • Assessment of TRAF4's interaction with SMURF1 and its effect on proteasomal degradation.

Main Results:

  • Low TRAF4 expression is significantly associated with poor overall survival in bladder cancer patients.
  • TRAF4 expression is epigenetically silenced and reduced by ERK-mediated phosphorylation in bladder cancer cells.
  • TRAF4 expression is inversely correlated with EMT markers and invasiveness; TRAF4 suppresses EMT and invasion.
  • High TRAF4 expression enhances BMP/SMAD signaling and inhibits NF-κB signaling, partly via targeting SMURF1 for degradation.
  • TRAF4 positively correlates with phospho-SMAD1/5 and negatively with phospho-NFκb-p65 in patient samples.

Conclusions:

  • TRAF4 acts as a tumor suppressor in bladder cancer, contrary to its role in other cancers.
  • TRAF4 regulates bladder cancer cell invasion and metastasis by modulating EMT and key signaling pathways.
  • TRAF4 is identified as a potential therapeutic target or predictive biomarker for bladder cancer progression.

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