Ulcerative Colitis: Black Raspberries May Decrease Progression to Colon Cancer

Li-Shu Wang, PhD Department of Medicine, Medical College of Wisconsin, Milwaukee, WisconsinMedicalResearch.com Interview with:
Li-Shu Wang, PhD
Department of Medicine, Medical College of Wisconsin,
Milwaukee, Wisconsin
MedicalResearch.com: What are the main findings of the study?

Answer: Ulcerative colitis (UC) is frequently an intermediate step to colon cancer.  The interleukin-10 knock-out (KO) mouse is a genetic model of this progression.  We have now shown that KO mice fed 5% black raspberries (BRBs) had significantly less colonic ulceration as compared to KO mice that consumed the control diet.  Dysfunction of the Wnt signaling pathway is a key event in UC-associated colon carcinogenesis.  We investigated the effects of BRBs on the Wnt pathway and found that the BRB-fed KO mice exhibited significantly decreased promoter methylation of Wnt antagonists and a significantly lower level of β-catenin nuclear translocation.  Our results suggest that BRBs inhibit colonic ulceration partly through inhibiting aberrant epigenetic events that dysregulate Wnt signaling.

MedicalResearch.com: Were any of the findings unexpected?

Answer: Wnt3a, a Wnt ligand gene, is associated with the regulation of Wnt pathway and repair.  Further, wnt3a is one of the most up-regulated genes so far known in inflamed human colon.  Our study showed that BRBs decreased promoter methylation of wnt3a and, interestingly they also decreased mRNA expression of wnt3a in colons from the KO mice.  This finding suggests that they decrease activation of wnt3a signaling.  These results agree with the observation that BRBs decreased -catenin nuclear localization; BRBs effectively inhibited the translocation of this transcription-regulating co-factor.  In addition, our results suggest other mechanisms are involved in regulating the expression of wnt3a.

MedicalResearch.com: What should clinicians and patients take away from your report?

Answer: Mesalamine is a mainstay therapeutic agent in human chronic ulcerative colitis; partly through decreasing -catenin activation which, in turn, decreases colitis-associated cancer.  Our data suggest that part of the mechanism of prevention by BRBs is by antagonizing the development of inappropriate epigenetic events and -catenin nuclear translocation which then correct dysregulated Wnt signaling at the onset of cancer development.  Overall our results lend credence to the supposition that including significant quantities of BRBs in the diet may reduce the risk of UC patients to develop colon cancer.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Answer: The IL-10 KO mouse model is a genetic animal model that recapitulates the genesis of human colon cancer that originates within a UC lesion.  Our current study shows that proper governance of the Wnt signaling pathway is maintained by BRBs by sustaining correct methylation patterns and expression of Wnt pathway negative regulatory genes.  Cancer chemoprevention by affecting histone modification and/or DNA methylation and DNMT1, DNMT3b, HDAC1, HDAC2, and MBD2 is a common observation.  We have now shown that ingestion of BRBs prevent the onset of their aberrant actions in the KO mice.  One question that remains, however, is whether BRBs prevent up regulation of DNMT1, DNMT3b, HDAC1, HDAC2, and MBD2, or cause their down regulation, or both.  Another question is whether they affect expression of these enzymes/proteins directly or indirectly.  We are currently searching for the answers to these questions.


Black Raspberries Protectively Regulate Methylation of Wnt Pathway Genes in Precancerous Colon Tissue

Li-Shu Wang, Chieh-Ti Kuo, Tim H. M. Huang, Martha Yearsley, Kiyoko Oshima, Gary D. Stoner, Jianhua Yu, John F. Lechner, and Yi-Wen Huang

Cancer Prev Res canprevres.0077.2013; Published OnlineFirst October 15, 2013; doi:10.1158/1940-6207.CAPR-13-0077

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