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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.

journal_name

Genes Dev

journal_title

Genes & development

authors

List K,Szabo R,Molinolo A,Sriuranpong V,Redeye V,Murdock T,Burke B,Nielsen BS,Gutkind JS,Bugge TH

doi

10.1101/gad.1300705

subject

Has Abstract

pub_date

2005-08-15 00:00:00

pages

1934-50

issue

16

eissn

0890-9369

issn

1549-5477

pii

19/16/1934

journal_volume

19

pub_type

杂志文章

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