期刊
INTERNATIONAL JOURNAL OF CANCER
卷 124, 期 5, 页码 1081-1089出版社
WILEY-LISS
DOI: 10.1002/ijc.24041
关键词
HNF-4 alpha; colorectal cancer; long chain fatty acids
类别
资金
- Israel Science Foundation [134/06]
Hepatocyte nuclear factor-4 alpha (HNIF-4 alpha) serves as target for fatty acid nutrients and xenobiotic amphipathic carboxylates and may account for the differential effects of dietary fatty acids on colorectal cancer (CRC). The putative role played by HNF-4 alpha in CRC has been verified here by evaluating the effect of HNF-4 alpha antagonists and HNIT-4 alpha siARNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF-4 alpha ligand antagonists of the MEDICA series, namely, beta,beta'-tetramethylhexadecanedioic acid (M16 beta beta) and gamma,gamma'-tetramethyloctadocanedioic acid (M18 gamma gamma) as well as HNF-4 alpha siRNA are shown here to inhibit growth and proliferation of HT29 and Caco2 CRC cells, accompanied by increased subG1 cell population, downregulated PCNA, activation of caspase-3, upregulation of Bak and cytoplasmic cytochrome-c, and downregulation of Bcl-2 resulting in apoptotic death. Inhibition of CRC growth with concomitant apoptosis was further confirmed in nude mice xenotransplanted with HT29 CRC cells. CRC suppression by HNF-4 alpha ligand antagonists and by HNF-4 alpha siRNA was accounted for by suppression of HNF-4 alpha transcription and protein expression. alpha,alpha'-tetrachlorotetradecanedioic acid (Cl-DICA), a MEDICA analogue that fails to suppress HNF-4 alpha, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF-4 alpha converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNIF-4 alpha activity by natural or xenobiotic HNF-4 alpha ligand antagonists or by HNF-4 alpha siARNA may offer a treatment mode for CRC. (c) 2008 Wiley-Liss, Inc.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据