Research from J. Pannequin and co-authors reveals new findings on gene therapy
2008 JAN 17 -- According to a study from Montpellier, France, "Aberrant activation of the (beta-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was in turn able to regulate beta-catenin/ Tcf-4 activity in adenomatous polyposis coli (APC)-mutated cells, and we analyzed the impact of topical progastrin depletion on intestinal tumor growth in vivo." "Stable or transient RNA silencing of the GAST gene was induced in human tumor cells and in mice carrying a heterozygous Apc mutation (APC Delta 14), which overexpress progastrin but not amidated or glycine-extended gastrin. Depletion of endogenous progastrin production strongly decreased intestinal tumor growth in vivo through a marked inhibition of constitutive beta-catenin/Tcf-4 activity in tumor cells. This effect was mediated by the de novo expression of the inhibitor of (beta-catenin and Tcf-4 (ICAT), resulting from a down-regulation of integrin-linked kinase in progastrin-depleted cells. Accordingly, ICAT down-regulation was correlated with progastrin overexpression and Tcf-4 target gene activation in human colorectal tumors, and ICAT repression was detected in the colon epithelium of tumor-prone, progastrin-overexpressing mice. In APC Delta 14 mice, small interfering RNA-mediated progastrin depletion not only reduced intestinal tumor size and numbers, but also increased goblet cell lineage differentiation and cell apoptosis in the remaining adenomas. Thus, depletion of endogenous progastrin inhibits the tumorigenicity of APC-mutated colorectal cancer cells in vivo by promoting ICAT expression, thereby counteracting Tcf-4 activity," wrote J. Pannequin and colleagues. The researchers concluded: "Progastrin targeting strategies should provide an exciting prospect for the differentiation therapy of colorectal cancer." Pannequin and colleagues published their study in Gastroenterology (beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Gastroenterology, 2007;133(5):1554-1568). For more information, contact F. Hollande, Institute Genom Fonct, Cellular & Molecular Oncology Department, 141 Rue Cardonille, F-34094 Montpellier 5, France. Publisher contact information for the journal Gastroenterology is: W B Saunders Co-Elsevier Inc., 1600 John F Kennedy Boulevard, Ste. 1800, Philadelphia, PA 19103-2899, USA. Keywords: France, Montpellier, Adenomatous Polyposis Coli, Biotechnology, Carcinogenesis, Colorectal, Drugs, Endocrinology, Gastroenterology, Gene Therapy, Glycine, Pharmaceuticals, Treatment. This article was prepared by Gene Therapy Weekly editors from staff and other reports. Copyright 2008, Gene Therapy Weekly via NewsRx.com.
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