MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis

摘要: The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance tumorigenesis not clear. We found that the incidence of carcinogen-induced skin tumors was substantially increased transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have abundance ligand HGF. Squamous also erupted spontaneously on mice were promoted by wounding or application 12-O-tetradecanoylphorbol 13-acetate, an activator protein C. Carcinogen-initiated had Ras mutations, spontaneous did not. Cultured keratinocytes from and oncogenic RAS-transduced shared phenotypic biochemical features initiation dependent autocrine activation epidermal factor (EGFR) through synthesis release EGFR ligands, mediated SRC, pseudoproteases iRhom1 iRhom2, metallopeptidase ADAM17. Pharmacological inhibition caused regression developed orthografts combined with dermal fibroblasts implanted onto syngeneic mice. global gene expression profile MET-transformed highly concordant RAS-transformed keratinocytes, a core RAS/MET coexpression network activated precancerous cancerous lesions. Tissue arrays revealed SCCs HGF at both transcript levels. Thus, EGFR, parallels RAS pathway to contribute mouse cutaneous cancers.