Epigenetic modulation of the retinoid X receptor α by green tea in the azoxymethane-ApcMin/+ mouse model of intestinal cancer

Suresh R. Volate, Stephanie J. Muga, Ala Y. Issa, Daniela Nitcheva, Theresa Smith, Michael J. Wargovich

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

We investigated the possible mechanisms of inhibition of colorectal carcinogenesis by green tea (GT) in azoxymethane-treated (AOM) Apc Min/+ mice. Mice received water or a 0.6% (w/v) solution of GT as the only source of beverage. GT treatment commenced at the 8th week of age and lasted for 8 wk. The treatment caused a statistically significant reduction in the number of newly formed tumors (28%, P<0.05). Immunohistochemical analysis showed that GT decreased the levels of β-catenin and its downstream target cyclin D1. To probe a mechanism, we further investigated the expression of retinoic X receptor alpha (RXRα) in AOM/ApcMin/+ tumors. Our results show that RXRα is selectively downregulated in AOM/Apc Min/+ mouse intestinal tumors. In contrast, other retinoic receptors including retinoic acid receptor alpha (RARα), RARβ, RXRβ, and RXRγ were all expressed in ApcMin/+ adenomas. Furthermore, our results show that RXRα downregulation is an early event in colorectal carcinogenesis and is independent of β-catenin expression. GT significantly increased the protein levels of RXRα. In addition, RT-PCR analysis showed that GT induced a similar increase in the levels of RXRα mRNA. Genomic bisulfite treatment of colonic DNA followed by pyrosequencing of 24 CpG sites in the promoter region of RXRα gene showed a significant decrease in CpG methylation with GT treatment. The results suggest that a low concentration of GT is sufficient to desilence RXRα and inhibit intestinal tumorigenesis in the ApcMin/+ mouse.

Original languageEnglish (US)
Pages (from-to)920-933
Number of pages14
JournalMolecular Carcinogenesis
Volume48
Issue number10
DOIs
StatePublished - Oct 2009
Externally publishedYes

Keywords

  • Apc mouse model
  • Azoxymethane (AOM)
  • Colon cancer
  • Cyclin D1
  • Green tea
  • Methylation
  • RXRα
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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