This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singh, P. Articles by Wood, T. Search for Related Content PubMed PubMed Citation Articles by Singh, P. Articles by Wood, T.

Gastrin Gene Expression Is Required for the Proliferation and Tumorigenicity of Human Colon Cancer Cells¹

Departments of Anatomy & Neurosciences [P. S., A. O., B. D.], Human Biological Chemistry & Genetics [P. S., T. W.], and Pathology [S. R.] and Sealy Center of Molecular Science [T. W.], The University of Texas Medical Branch, Galveston, Texas 77555-1043, and Department of Physiology, The University of Liverpool, Liverpool, United Kingdom [A. V.]

The majority of human colon cancers express the gastrin gene, and a significant percentage bind gastrin-like peptides. However, it is not known if gastrin gene products are physiologically relevant to the growth and proliferation of human colon cancers. To investigate the functional role of gastrin gene expression, we examined the effect of gastrin antisense (AS) RNA expression on the growth and tumorigenicity of colon cancer cells. The full-length human gastrin cDNA was cloned in the AS direction in a retroviral vector under the transcriptional control of human cytomegalovirus promoter. Three representative human colon cancer cell lines that expressed negligible (Colo-205A) to significant (Colo-320 and HCT-116) levels of gastrin mRNA were transfected with either AS or control vectors and subjected to various growth studies in vitro and in vivo. The proliferative and tumorigenic potential of the AS clones from the gastrin-expressing cell lines was significantly suppressed compared to that of the control clones, whereas the growth of Colo-205A-AS cells (the negative control) was similar to that of the Colo-205A-C-cells, indicating the relative specificity of the antitumorigenic effects of AS gastrin RNA expression. We believe that this is the first evidence that supports a possible critical role of gastrin gene expression in the tumorigenicity of human colon cancers that express the gastrin gene. Because >60–80% of human colon cancers express the gastrin gene, it can be expected that the growth of a significant percentage of these cancers may be critically dependent on the expression of gastrin gene products. Therapeutic measures, such as the AS strategy used in the present study, may therefore prove to be useful in treating human colon cancers in the future.

¹ Supported by grants from the NIH (CA60087) and John Sealy Memorial Endowment Funds (440700).

² To whom requests for reprints should be addressed, at Departments of Anatomy & Neurosciences and Human Biological Chemistry & Genetics, 10.138 Medical Research Building, 1043. The University of Texas Medical Branch, Galveston, TX 77555-1043. Phone: (409) 772-4842; Fax: (409) 772-1861; E-mail: psingh@mbian.utmb.edu.

Received 5/24/96. Accepted 7/24/96.

This article has been cited by other articles:

				P. Timmerman, R. Barderas, J. Desmet, D. Altschuh, S. Shochat, M. J. Hollestelle, J. W. M. Hoppener, A. Monasterio, J. I. Casal, and R. H. Meloen A Combinatorial Approach for the Design of Complementarity-determining Region-derived Peptidomimetics with in Vitro Anti-tumoral Activity J. Biol. Chem., December 4, 2009; 284(49): 34126 - 34134. [Abstract] [Full Text] [PDF]

				D. Subramaniam, R. May, S. M. Sureban, K. B. Lee, R. George, P. Kuppusamy, R. P. Ramanujam, K. Hideg, B. K. Dieckgraefe, C. W. Houchen, et al. Diphenyl Difluoroketone: A Curcumin Derivative with Potent In vivo Anticancer Activity Cancer Res., March 15, 2008; 68(6): 1962 - 1969. [Abstract] [Full Text] [PDF]

				W. Rengifo-Cam, S. Umar, S. Sarkar, and P. Singh Antiapoptotic Effects of Progastrin on Pancreatic Cancer Cells Are Mediated by Sustained Activation of Nuclear Factor-{kappa}B Cancer Res., August 1, 2007; 67(15): 7266 - 7274. [Abstract] [Full Text] [PDF]

				S. Lei, A. Dubeykovskiy, A. Chakladar, L. Wojtukiewicz, and T. C. Wang The Murine Gastrin Promoter Is Synergistically Activated by Transforming Growth Factor-{beta}/Smad and Wnt Signaling Pathways J. Biol. Chem., October 8, 2004; 279(41): 42492 - 42502. [Abstract] [Full Text] [PDF]

				H. Wu, A. Owlia, and P. Singh Precursor peptide progastrin1-80 reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP Am J Physiol Gastrointest Liver Physiol, December 1, 2003; 285(6): G1097 - G1110. [Abstract] [Full Text] [PDF]

				R. P. Thomas, M. R. Hellmich, C. M. Townsend Jr., and B. M. Evers Role of Gastrointestinal Hormones in the Proliferation of Normal and Neoplastic Tissues Endocr. Rev., October 1, 2003; 24(5): 571 - 599. [Abstract] [Full Text] [PDF]

				P. Singh, X. Lu, S. Cobb, B. T. Miller, N. Tarasova, A. Varro, and A. Owlia Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites Am J Physiol Gastrointest Liver Physiol, February 1, 2003; 284(2): G328 - G339. [Abstract] [Full Text] [PDF]

				D. Brown, U. Yallampalli, A. Owlia, and P. Singh pp60c-Src Kinase Mediates Growth Effects of the Full-Length Precursor Progastrin1-80 Peptide on Rat Intestinal Epithelial Cells, in Vitro Endocrinology, January 1, 2003; 144(1): 201 - 211. [Abstract] [Full Text] [PDF]

				A Varro, P J Noble, L E Wroblewski, L Bishop, and G J Dockray Gastrin-cholecystokininB receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor Gut, June 1, 2002; 50(6): 827 - 833. [Abstract] [Full Text] [PDF]

				E. Ofori-Darko, Y. Zavros, G. Rieder, S. A. Tarle, M. Van Antwerp, and J. L. Merchant An OmpA-Like Protein from Acinetobacter spp. Stimulates Gastrin and Interleukin-8 Promoters Infect. Immun., June 1, 2000; 68(6): 3657 - 3666. [Abstract] [Full Text] [PDF]

				P. Singh, M. Velasco, R. Given, M. Wargovich, A. Varro, and T. C. Wang Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM Am J Physiol Gastrointest Liver Physiol, March 1, 2000; 278(3): G390 - G399. [Abstract] [Full Text] [PDF]

				V. M. Stepan, D. F. Krametter, M. Matsushima, A. Todisco, J. Delvalle, and C. J. Dickinson Glycine-extended gastrin regulates HEK cell growth Am J Physiol Regulatory Integrative Comp Physiol, August 1, 1999; 277(2): R572 - R581. [Abstract] [Full Text] [PDF]

				G J Dockray Gastrin and gastric epithelial physiology J. Physiol., July 15, 1999; 518(2): 315 - 324. [Abstract] [Full Text] [PDF]

				I Hussain, G W Bate, J Henry, P Djali, R Dimaline, G J Dockray, and A Varro Modulation of gastrin processing by vesicular monoamine transporter type 1 (VMAT1) in rat gastrin cells J. Physiol., June 1, 1999; 517(2): 495 - 505. [Abstract] [Full Text] [PDF]

				Y.-L. Dong, L. Fang, P.R.R. Gangula, and C. Yallampalli Regulation of Inducible Nitric Oxide Synthase Messenger Ribonucleic Acid Expression in Pregnant Rat Uterus Biol Reprod, October 1, 1998; 59(4): 933 - 940. [Abstract] [Full Text]

				G S BALDWIN and A SHULKES Gastrin, gastrin receptors and colorectal carcinoma Gut, April 1, 1998; 42(4): 581 - 584. [Full Text] [PDF]

				H. Wu, G. N. Rao, B. Dai, and P. Singh Autocrine Gastrins in Colon Cancer Cells Up-regulate Cytochrome c Oxidase Vb and Down-regulate Efflux of Cytochrome c and Activation of Caspase-3 J. Biol. Chem., October 13, 2000; 275(42): 32491 - 32498. [Abstract] [Full Text] [PDF]

				G. S. Baldwin, F. Hollande, Z. Yang, Y. Karelina, A. Paterson, R. Strang, D. Fourmy, G. Neumann, and A. Shulkes Biologically Active Recombinant Human Progastrin6-80 Contains a Tightly Bound Calcium Ion J. Biol. Chem., March 9, 2001; 276(11): 7791 - 7796. [Abstract] [Full Text] [PDF]