Journal
ONCOTARGET
Volume 7, Issue 14, Pages 17870-17884Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7554
Keywords
genistein-27; colitis-associated cancer; CDX2; beta-catenin; chemoprevention
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Funding
- Natural Science Foundation of China [81372268, 81173087, 81202611]
- Natural Science Foundation for Distinguished Young Scholars of Jiangsu Province [BK20130026]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [ZJ11173]
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Nonresolving inflammation in the intestine predisposes individuals to colitis-associated colorectal cancer (CAC), which leads to high morbidity and mortality. Here we show that genistein-27 (GEN-27), a derivative of genistein, inhibited proliferation of human colorectal cancer cells through inhibiting beta-catenin activity. Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced beta-catenin nuclear localization, which resulted from the inhibition of NF-kappa B/p65 nuclear localization and up-regulation of caudal-related homeobox transcription factor 2 (CDX2). Furthermore, GEN-27 decreased binding of p65 to the silencer region of CDX2 and increased binding of CDX2 to the promoter regions of APC and AXIN2, thus inhibiting the activation of beta-catenin induced by TNF-alpha. Importantly, GEN-27 protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and tumor volume. Histopathology, immunohistochemistry and flow cytometry revealed that dietary GEN-27 significantly decreased secretion of proinflammatory cytokines and macrophage infiltration. Moreover, GEN-27 inhibited AOM/DSS-induced p65 and beta-catenin nuclear translocation, while promoted the expression of CDX2, APC, and AXIN2. Taken together, our findings demonstrate that the anti-proliferation effect of GEN-27 in vitro and the prevention of CAC in vivo is mediated by p65-CDX2-beta-catenin axis via inhibiting beta-catenin target genes. Our results imply that GEN-27 could be a promising candidate for the chemoprevention of CAC.
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