Oncotarget

Research Papers:

Chemopreventive activity of GEN-27, a genistein derivative, in colitis-associated cancer is mediated by p65-CDX2-β-catenin axis

Qianming Du, Yajing Wang, Chao Liu, Hong Wang, Huimin Fan, Yan Li, Jianing Wang, Xu Zhang, Jinrong Lu, Hui Ji and Rong Hu _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:17870-17884. https://doi.org/10.18632/oncotarget.7554

Metrics: PDF 2983 views  |   HTML 1321 views  |   ?  


Abstract

Qianming Du1,*, Yajing Wang1,*, Chao Liu1,*, Hong Wang1, Huimin Fan1, Yan Li2, Jianing Wang3, Xu Zhang4, Jinrong Lu5, Hui Ji1 and Rong Hu1

1 State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Jiangsu, Nanjing, P.R. China

2 Department of Chronic Communicable Disease, Jiangsu Provincial Center for Disease Prevention and Control, Jiangsu, Nanjing, P.R.China

3 Neurobiology Laboratory, Jiangsu Center for Drug Screening, China Pharmaceutical University, Jiangsu, Nanjing, P.R.China

4 College of Clinical Medicine, Chengdu University of TCM, Chengdu, P.R. China

5 Department of Organic Chemistry, China Pharmaceutical University, Jiangsu, Nanjing, P.R. China

* These authors have contributed equally to this work

Correspondence to:

Rong Hu, email:

Hui Ji, email:

Keywords: genistein-27, colitis-associated cancer, CDX2, β-catenin, chemoprevention

Received: October 26, 2015 Accepted: February 11, 2016 Published: February 21, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 7554