MET signaling in keratinocytes activates EGFR and initiates squamous carcinogenesis
Autor: | Aleksandra M. Michalowski, Shelley B. Hoover, Jennifer E. Dwyer, Anne Zhuang, Andrew Ryscavage, Stuart H. Yuspa, Mark Simpson, Mary Klosterman, Kameron B. Rodrigues, Lisa Wright, Fan Liu, Kelly Shibuya, Glenn Merlino, Wendy Dubois, Christophe Cataisson |
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Rok vydání: | 2016 |
Předmět: |
Keratinocytes
0301 basic medicine medicine.medical_specialty Skin Neoplasms Human skin medicine.disease_cause Biochemistry Article Receptor tyrosine kinase Mice 03 medical and health sciences Internal medicine medicine Animals Humans Epidermal growth factor receptor Protein kinase A Autocrine signalling Molecular Biology biology Cell Biology Proto-Oncogene Proteins c-met ErbB Receptors Gene Expression Regulation Neoplastic 030104 developmental biology Endocrinology Carcinoma Squamous Cell Cancer research biology.protein Tetradecanoylphorbol Acetate Signal transduction Carcinogenesis Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
Zdroj: | Science Signaling. 9 |
ISSN: | 1937-9145 1945-0877 |
Popis: | The receptor tyrosine kinase MET is abundant in many human squamous cell carcinomas (SCCs), but its functional significance in tumorigenesis is not clear. We found that the incidence of carcinogen-induced skin squamous tumors was substantially increased in transgenic MT-HGF (mouse metallothionein-hepatocyte growth factor) mice, which have increased abundance of the MET ligand HGF. Squamous tumors also erupted spontaneously on the skin of MT-HGF mice that were promoted by wounding or the application of 12-O-tetradecanoylphorbol 13-acetate, an activator of protein kinase C. Carcinogen-initiated tumors had Ras mutations, but spontaneous tumors did not. Cultured keratinocytes from MT-HGF mice and oncogenic RAS-transduced keratinocytes shared phenotypic and biochemical features of initiation that were dependent on autocrine activation of epidermal growth factor receptor (EGFR) through increased synthesis and release of EGFR ligands, which was mediated by the kinase SRC, the pseudoproteases iRhom1 and iRhom2, and the metallopeptidase ADAM17. Pharmacological inhibition of EGFR caused the regression of MT-HGF squamous tumors that developed spontaneously in orthografts of MT-HGF keratinocytes combined with dermal fibroblasts and implanted onto syngeneic mice. The global gene expression profile in MET-transformed keratinocytes was highly concordant with that in RAS-transformed keratinocytes, and a core RAS/MET coexpression network was activated in precancerous and cancerous human skin lesions. Tissue arrays revealed that many human skin SCCs have abundant HGF at both the transcript and protein levels. Thus, through the activation of EGFR, MET activation parallels a RAS pathway to contribute to human and mouse cutaneous cancers. |
Databáze: | OpenAIRE |
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