title: A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion.
abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive forms of human cancer with poor prognosis due to late diagnosis and metastasis. Common genomic alterations in ESCC include p53 mutation, p120ctn inactivation, and overexpression of oncogenes such as cyclin D1, EGFR, and c-Met. Using esophageal epithelial cells transformed by the overexpression of EGFR and p53(R175H), we find novel evidence of a functional link between p53(R175H) and the c-Met receptor tyrosine kinase to mediate tumor cell invasion. Increased c-Met receptor activation was observed upon p53(R175H) expression and enhanced further upon subsequent EGFR overexpression. We inhibited c-Met phosphorylation, resulting in diminished invasion of the genetically transformed primary esophageal epithelial cells (EPC-hTERT-EGFR-p53(R175H)), suggesting that the mechanism of increased invasiveness upon EGFR and p53(R175H) expression may be the result of increased c-Met activation. These results suggest that the use of therapeutics directed at c-Met in ESCC and other squamous cell cancers.
authors.affiliation: Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Katharine D
authors.initials: KD
authors.lastname: Grugan
authors.affiliation: Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Vega
authors.affiliation: Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Wong
authors.affiliation: The Abramson Family Cancer Research Institute; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: J Alan
authors.initials: JA
authors.lastname: Diehl
authors.affiliation: Department of Medical Oncology; Dana Farber Cancer Institute; Boston, MA USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Department of Medical Oncology; Dana Farber Cancer Institute; Boston, MA USA.
authors.forename: Kwok K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Gastroenterology Division; Department of Medicine; University of Pennsylvania; Philadelphia, PA USA; Abramson Cancer Center; University of Pennsylvania; Philadelphia, PA USA; Department of Genetics; University of Pennsylvania; Philadelphia, PA USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met; esophageal cancer; p53 mutation; tumor invasion