GASTRIN GENE-EXPRESSION IS REQUIRED FOR THE PROLIFERATION AND TUMORIGENICITY OF HUMAN COLON-CANCER CELLS

The majority of human colon cancers express the gastrin gene, and a si gnificant percentage bind gastrin-like peptides, However, it is not kn own if gastrin gene products are physiologically relevant to the growt h and proliferation of human colon cancers, To investigate the functio nal role of gastrin gene expression, we examined the effect of gastrin antisense (AS) RNA expression on the growth and tumorigenicity of col on cancer cells. The full-length human gastrin cDNA was cloned in the AS direction in a retroviral vector under the transcriptional control of human cytomegato-virus promoter, Three representative human colon c ancer cell lines that expressed negligible (Colo-205A) to significant (Colo-320 and HCT-116) levels of gastrin mRNA were transfected with ei ther 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 sup pressed compared to that of the control clones, whereas the growth of Colo-205A-AS cells (the negative control) was similar to that of the C olo-205A-C-cells, indicating the relative specificity of the antitumor igenic effects of AS gastrin RNA expression, We believe that this is t he first evidence that supports a possible critical role of gastrin ge ne expression in the tumorigenicity of human colon cancers that expres s the gastrin gene, Because >60-80% of human colon cancers express the gastrin gene, it can be expected that the growth of a significant per centage of these cancers may be critically dependent on the expression of gastrin gene products, Therapeutic measures, such as the AS strate gy used in the present study, may therefore prove to be useful in trea ting human colon cancers in the future.