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

Area of Science:

• Oncology
• Molecular Biology
• Gastroenterology

Background:

• Gastrointestinal (GI) cancers exhibit aberrant expression of cholecystokinin-2 (CCK2)/gastrin receptor splice variants.
• The functional impact of these variants on cancer development remains largely uncharacterized.

Purpose of the Study:

• To investigate and compare the in vitro and in vivo effects of CCK2 receptor (CCK2R) and CCK2i4svR expression on human epithelial cell growth.
• To elucidate the molecular mechanisms underlying the differential impact of these receptor variants on tumorigenesis.

Main Methods:

• Utilized a human epithelial cell model (HEK293) to express CCK2R and CCK2i4svR variants.
• Assessed cell proliferation in vitro under varying conditions (agonist presence/absence).
• Evaluated tumor growth, Src-dependent signaling, hypoxia-inducible factor-1alpha (HIF-1α) levels, vascular endothelial growth factor (VEGF) expression, and tumor micro-vessel density in vivo.

Main Results:

• In vitro, neither CCK2R nor CCK2i4svR expression affected cell proliferation.
• In vivo, CCK2i4svR expression, but not CCK2R, constitutively increased HEK293 tumor growth in a Src-dependent manner.
• CCK2i4svR-mediated tumorigenicity correlated with increased HIF-1α, VEGF, and tumor micro-vessel density, indicating enhanced angiogenesis.

Conclusions:

• The CCK2i4svR splice variant promotes GI cancer growth and tumorigenicity through agonist-independent, Src-dependent mechanisms.
• CCK2i4svR enhances tumor angiogenesis by upregulating the HIF-1α/VEGF pathway.
• These findings suggest CCK2i4svR as a potential therapeutic target for modulating GI cancer progression and metastasis.