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Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin

Topi A Tervonen1, Shishir M Pant1, Denis Belitškin1

  • 1Research Programs Unit/Translational Cancer Medicine and Medicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Cancer Research
|January 19, 2021
PubMed

Insights

Oncogenic Ras activates the protease hepsin, which drives cancer invasion by degrading epithelial integrity and the basement membrane. Inhibiting hepsin may offer a therapeutic strategy for Ras-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Ras proteins are key drivers of cancer growth and invasion.
  • The precise mechanisms by which Ras initiates tumor invasion, including loss of epithelial integrity and basement membrane breaching, remain unclear.

Purpose of the Study:

  • To investigate the role of Ras in initiating early invasion features.
  • To identify molecular targets of Ras involved in disrupting epithelial structure and basement membrane integrity.

Main Methods:

  • Utilized Ras-transformed three-dimensional mammary epithelial cultures.
  • Employed gene silencing techniques to ablate hepsin function.
  • Analyzed tumor xenografts with mutant KRas.
  • Investigated signaling pathways including Raf-MEK-ERK and heat shock transcription factor-1.

Main Results:

  • Oncogenic Ras strongly activates hepsin, a serine protease, via the Raf-MEK-ERK pathway and heat shock transcription factor-1.
  • Hepsin ablation in Ras-transformed cells restored desmosomal junctions, hemidesmosomes, basement membrane integrity, and epithelial cohesion.
  • Silencing hepsin in KRas-mutant tumor xenografts increased local invasion and collagen IV accumulation.

Conclusions:

  • Hepsin is a critical protease in Ras-dependent tumorigenesis, mediating pathologies in cell-cell and cell-matrix interactions essential for early tumor spread.
  • Hepsin represents a potential therapeutic target for Ras-driven cancers due to its role in disrupting epithelial structure and promoting invasion.

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