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

Oncogene volume 26, pages 1013–1019 (2007)Cite this article

Abstract

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 CCK2i4svR 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 CCK2i4svR, but not CCK2R, increases HEK293 tumor growth in a constitutive, Src-dependent manner. Enhanced tumorigenicity of CCK2i4svR 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 CCK2i4svR may contribute to the growth and spread of GI cancers through agonist-independent mechanisms that enhance tumor angiogenesis.

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Acknowledgements

We thank Drs Sarah J Parsons (University of Virginia Health System, VA) for the plasmid containing the kinase-dead Src mutant (A430V) cDNA. We also thank Eileen Figueroa, Steve Schuenke, Michael Knight and Karen Martin for their assistance in the preparation of this manuscript. This work is supported by grants from the National Institutes of Health (R01 DK48345 and R01 DK58119) and Sealy Grant (CON14347).

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Authors and Affiliations

  1. Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA

    C Chao, E Goluszko, Y-T Lee, T Uchida, C M Townsend Jr & M R Hellmich

  2. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA

    A A Kolokoltsov & R A Davey

  3. Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX, USA

    C Chao & M R Hellmich

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  1. C Chao
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  2. E Goluszko
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Correspondence to M R Hellmich.

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Chao, C., Goluszko, E., Lee, YT. et al. Constitutively active CCK2 receptor splice variant increases Src-dependent HIF-1α expression and tumor growth. Oncogene 26, 1013–1019 (2007). https://doi.org/10.1038/sj.onc.1209862

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