Constitutively active CCK₂ receptor splice variant increases Src-dependent HIF-1α expression and tumor growth

Gastrointestinal (GI) cancers ectopically express multiple splice variants of the cholecystokinin-2 (CCK₂)/gastrin receptor; however, their relative contributions to the cancer phenotype are unknown. The aim of this study was to compare the effects of CCK₂ receptor (CCK₂R) and CCK_2i4svR expression on cell growth both in vitro and in vivo using a human epithelial cell model, HEK239. In vitro, receptor variant expression did not affect cell proliferation either in the absence or presence of agonist. However, in vivo, the expression of CCK_2i4svR, but not CCK₂R, increases HEK293 tumor growth in a constitutive, Src-dependent manner. Enhanced tumorigenicity of CCK_2i4svR is associated with an Src-dependent increase in the transcription factor, hypoxia-inducible factor-1α, its downstream target, vascular endothelial growth factor and tumor micro-vessel density, suggesting that CCK_2i4svR may contribute to the growth and spread of GI cancers through agonist-independent mechanisms that enhance tumor angiogenesis.