Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation.

Abstract

Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K-Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation.

• Authors: Karin List, Roman Szabo, Alfredo Molinolo, Virote Sriuranpong, Vivien Redeye, Tricia Murdock, Beth Burke, Boye S Nielsen, J Silvio Gutkind, Thomas H Bugge
• Journal: Genes & development (Genes Dev) Vol. 19 Issue 16 Pg. 1934-50 (Aug 15 2005) ISSN: 0890-9369 [Print] United States
• PMID: 16103220 (Publication Type: Journal Article)

Chemical References

• Carcinogens
• Membrane Glycoproteins
• Proteinase Inhibitory Proteins, Secretory
• SPINT1 protein, human
• Serine Proteinase Inhibitors
• Spint1 protein, mouse
• 9,10-Dimethyl-1,2-benzanthracene
• Phosphatidylinositol 3-Kinases
• Protein Kinase C
• Serine Endopeptidases
• matriptase
• ras Proteins

Topics

• 9,10-Dimethyl-1,2-benzanthracene (pharmacology)
• Animals
• Carcinogens (pharmacology)
• Carcinoma, Squamous Cell (pathology, secondary)
• Cell Transformation, Neoplastic (chemically induced, genetics, metabolism)
• Epidermis (metabolism)
• Humans
• Lymph Nodes (pathology)
• Membrane Glycoproteins (genetics, physiology)
• Mice
• Mice, Transgenic
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase C (metabolism)
• Proteinase Inhibitory Proteins, Secretory
• Serine Endopeptidases (genetics, metabolism, physiology)
• Serine Proteinase Inhibitors (genetics, physiology)
• ras Proteins (physiology)