Abstract
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 β-catenin activity. Our results showed that GEN-27 increased expressions of adenomatous polyposis coli (APC) and axis inhibition protein 2 (AXIN2), and reduced β-catenin nuclear localization, which resulted from the inhibition of NF-κB/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 β-catenin induced by TNF-α. 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 β-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-β-catenin axis via inhibiting β-catenin target genes. Our results imply that GEN-27 could be a promising candidate for the chemoprevention of CAC.
Highlights
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the second leading cause of cancer related deaths in the United States [1]
We demonstrated that GEN-27 significantly inhibited proliferation of human colorectal cancer cells through inhibiting the activity of p65CDX2-β-catenin axis
In order to access the effect of GEN-27 in human relevant models, human colorectal carcinoma cell lines HCT116, HT29, SW620 and normal colon epithelial cell line FHC were treated with varying concentrations of GEN-27 for 24h (Figure 1B)
Summary
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the second leading cause of cancer related deaths in the United States [1]. It has been shown that patients suffering from inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn disease, are at increased risk of developing CRC www.impactjournals.com/oncotarget [5,6,7]. Inactivation of the APC/AXIN/GSK-3β complex causes β-catenin accumulation in the cytosol and its translocation into the nucleus, where it acts as a co‐activator for TCF/LEF-mediated transcription and modulates cell proliferation, survival and differentiation [11]. This destruction complex thereby controls the proliferation of colon cells by maintaining the level of active β-catenin
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