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Targeted suppression of beta-catenin blocks intestinal adenoma formation in APC Min mice.

AbstractINTRODUCTION:
Mutations involving the adenomatous polyposis coli (APC) tumor suppressor gene leading to activation of beta-catenin have been identified in the majority of sporadic colonic adenocarcinomas and in essentially all colonic tumors from patients with Familial Adenomatous Polyposis. The C57BL/6J-APC(min) (Min) mouse, which carries a germ line mutation in the murine homolog of the APC gene is a useful model for intestinal adenoma formation linked to loss of APC activity. One of the critical downstream molecules regulated by APC is beta-catenin; molecular targeting of beta-catenin is, thus, an attractive chemopreventative strategy in colon cancer. Antisense oligodeoxynucleotides (AODNs) capable of downregulating murine beta-catenin have been identified. ANALYSIS OF beta-CATENIN PROTEIN EXPRESSION IN LIVER TISSUE AND INTESTINAL ADENOMAS: Adenomas harvested from mice treated for 7 days with beta-catenin AODNs demonstrated clear downregulation of beta-catenin expression, which was accompanied by a significant reduction in proliferation. There was no effect on proliferation in normal intestinal epithelium. Min mice treated systemically with beta-catenin AODNs over a 6-week period had a statistically significant reduction in the number of intestinal adenomas. These studies provide direct evidence that targeted suppression of beta-catenin inhibits the formation of intestinal adenomas in APC-mutant mice. Furthermore, these studies suggest that molecular targeting of beta-catenin holds significant promise as a chemopreventative strategy in colon cancer.
AuthorsPaul J Foley, Randall P Scheri, Christopher J Smolock, James Pippin, Douglas W Green, Jeffrey A Drebin
JournalJournal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract (J Gastrointest Surg) Vol. 12 Issue 8 Pg. 1452-8 (Aug 2008) ISSN: 1873-4626 [Electronic] United States
PMID18521697 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CTNNB1 protein, mouse
  • RNA, Neoplasm
  • beta Catenin
Topics
  • Adenomatous Polyposis Coli (genetics, metabolism, therapy)
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Cell Proliferation
  • Colonic Neoplasms (genetics, metabolism, therapy)
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Targeting (methods)
  • Immunohistochemistry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental
  • RNA, Neoplasm (genetics)
  • Treatment Outcome
  • beta Catenin (genetics, metabolism)

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