Abstract
The roles of cholecystokinin 2 receptor (CCK2R) in numerous physiologic processes in the gastrointestinal tract and central nervous system are well documented. There has been some evidence that CCK2R alterations play a role in cancers, but the functional significance of these alterations for tumorigenesis is unknown. We have identified six mutations in CCK2R among a panel of 140 colorectal cancers and 44 gastric cancers. We show that these mutations increase receptor activity, activate multiple downstream signaling pathways, increase cell migration, and promote angiogenesis. Our findings suggest that somatic mutations in CCK2R may promote tumorigenesis through deregulated receptor activity and highlight the importance of evaluating CCK2R inhibitors to block both the normal and mutant forms of the receptor.
2012 AACR
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Movement / genetics
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Cell Shape / genetics
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism
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Cells, Cultured
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Coculture Techniques
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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DNA Mutational Analysis
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Endothelial Cells / metabolism
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Endothelial Cells / physiology
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HEK293 Cells
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Humans
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Immunoblotting
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Mice
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Microscopy, Fluorescence
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Mutation*
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NIH 3T3 Cells
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Neovascularization, Pathologic / genetics
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / physiopathology
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Neovascularization, Physiologic / genetics
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Neovascularization, Physiologic / physiology
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Phenotype
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RNA Interference
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Receptor, Cholecystokinin B / genetics*
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Receptor, Cholecystokinin B / metabolism
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Receptor, Cholecystokinin B / physiology
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Stomach Neoplasms / genetics*
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology
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Transfection
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Receptor, Cholecystokinin B
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Vascular Endothelial Growth Factor A