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.

Keywords: :

• p53 mutation
• c-Met
• esophageal cancer
• tumor invasion

This article is referred to by:

Non-canonical p53 signaling to promote invasion

Disclosure of Potential Conflicts of Interest

The authors have no conflicts of interest to disclose.

Acknowledgments

The authors would like to thank the members of the Rustgi lab for technical support and helpful discussions. This work was supported by NIH/NCI P01 CA098101, NIH/NCI U01 CA 143056, NIH/NIDDK P30 DK050306 Center for Molecular Studies in Digestive and Liver Diseases (and Molecular Pathology and Imaging, Molecular Biology/Gene Expression, Cell Culture Core Facilities), American Cancer Society Grant RP-10-033-01-CCE (AKR) NIH T32 NIH/NRSA F32 DK082149 (KDG), NIH T32 CA09140 (MEV), and NIH T32 CA115299 (GSW).