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

Cancer Res. 2021 Mar 15;81(6):1513-1527. doi: 10.1158/0008-5472.CAN-20-1760. Epub 2021 Jan 18.


Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf-MEK-ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell-cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell-cell and cell-matrix pathologies important for early tumor dissemination. SIGNIFICANCE: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell-cell and cell-matrix interactions and cohesion of epithelial structure.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basement Membrane / cytology
  • Basement Membrane / pathology
  • Breast / pathology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Carcinogenesis / pathology
  • Cell Communication
  • Cell Line, Tumor
  • Collagen Type IV / metabolism
  • Desmosomes / pathology
  • Epithelial Cells / cytology
  • Epithelial Cells / pathology*
  • Female
  • Gene Knockdown Techniques
  • Heat Shock Transcription Factors / genetics
  • Heat Shock Transcription Factors / metabolism*
  • Humans
  • MAP Kinase Signaling System / genetics
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Mice, Transgenic
  • Mutation
  • Neoplasm Invasiveness / pathology
  • Primary Cell Culture
  • Protein Stability
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Up-Regulation
  • Xenograft Model Antitumor Assays


  • Collagen Type IV
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • KRAS protein, human
  • Serine Endopeptidases
  • HPN protein, human
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)