Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation.
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.
List
Karin
K
Proteases and Tissue Remodeling Unit, Molecular Carcinogenesis Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Szabo
Roman
R
Molinolo
Alfredo
A
Sriuranpong
Virote
V
Redeye
Vivien
V
Murdock
Tricia
T
Burke
Beth
B
Nielsen
Boye S
BS
Gutkind
J Silvio
JS
Bugge
Thomas H
TH
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000556:secondary; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D002273:Carcinogens; D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D015842:Serine Proteinase Inhibitors; C504591:Spint1 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D012697:Serine Endopeptidases; C485595:matriptase; D018631:ras Proteins