Deregulation of
matriptase is a consistent feature of human epithelial
cancers and correlates with poor disease outcome. We have previously shown that
matriptase promotes multi-stage squamous cell
carcinogenesis in transgenic mice through dual activation of
pro-hepatocyte growth factor-cMet-Akt-mTor proliferation/survival signaling and PAR-2-Gαi-NFκB inflammatory signaling.
Matriptase was congenitally and constitutively deregulated in our prior studies, and therefore it was unclear if aberrant
matriptase signaling supports only initiation of
tumor formation or if it is also critical for the progression of established
tumors. To determine this, we here have generated triple-transgenic mice with constitutive deregulation of
matriptase and simultaneous inducible expression of the cognate
matriptase inhibitor,
hepatocyte growth factor inhibitor (HAI)-2. As expected, constitutive expression of HAI-2 suppressed the formation of
matriptase-dependent
tumors in 7,12-Dimethylbenz(a)anthracene-treated mouse skin. Interestingly, however, the induction of HAI-2 expression in already established
tumors markedly impaired malignant progression and caused regression of individual
tumors.
Tumor regression correlated with reduced accumulation of
tumor-associated inflammatory cells, likely caused by diminished expression of pro-tumorigenic inflammatory
cytokines. The data suggest that
matriptase-dependent signaling may be a therapeutic target for both
squamous cell carcinoma chemoprevention and for the treatment of established
tumors.