SMAD7 in keratinocytes promotes skin carcinogenesis by activating ATM-dependent DNA repair and an EGFR-mediated cell proliferation pathway

Abstract

SMAD7 promotes skin carcinogenesis by enhancing the ATM-NBS1-mediated DNA repair pathway and attenuating c-Cbl-mediated EGFR degradation in an in vivo mouse models. In agreement with the mechanistic analysis, inhibition of EGFR signaling with cetuximab attenuated the SMAD7-promoted tumor formation. Abstract SMA- and MAD-related protein 7 (SMAD7) is a general inhibitor of transforming growth factor- (TGF-) signaling that acts through interaction and degradation of TGF- receptors. SMAD7 has been demonstrated to be transcriptionally upregulated in chemical-induced skin tumors and TGF--treated normal keratinocytes. To evaluate the function of SMAD7 in skin carcinogenesis in vivo, Smad7 transgenic mice that specifically express either wild-type (WT) SMAD7 (TG-Smad7-WT) or mutant SMAD7 (TG-Smad7-MT) in keratinocytes, as well as Smad7 keratinocyte-specific knockout (Smad7(2f/2f)-K14Cre) mice, were subjected to chemical-induced skin carcinogenesis. WT-SMAD7-expressing transgenic mice showed significantly greater papilloma formation than did non-TG control and Smad7-MT mice. The expression of WT-SMAD7 attenuated DNA damage-induced apoptosis in epidermal keratinocytes by stimulating the ATM-dependent DNA repair pathway. Nonetheless, overexpression of WT-SMAD7 caused a susceptibility to 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperproliferation through activation of epidermal growth factor (EGF) signaling. In agreement with the transgenic mouse data, keratinocyte-specific deletion of SMAD7 markedly suppressed the tumor formation by inhibiting ATM and epidermal growth factor receptor (EGFR) signaling. Moreover, specific inhibition of EGFR signaling attenuated the hyperproliferation and tumor formation in TG-Smad7-WT mice. Taken together, these data support a novel role for SMAD7 as a tumor promoter in skin carcinogenesis where SMAD7 stimulates the DNA repair pathway and EGFR signaling activation.