Schwartz Betty, Algamas-Dimantov Anna, Hertz Rachel, Nataf Jennifer, Kerman Ayelet, Peri Irena, Bar-Tana Jacob
The Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Int J Cancer. 2009 Mar 1;124(5):1081-9. doi: 10.1002/ijc.24041.
Hepatocyte nuclear factor-4alpha (HNF-4alpha) 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-4alpha in CRC has been verified here by evaluating the effect of HNF-4alpha antagonists and HNF-4alpha siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF-4alpha ligand antagonists of the MEDICA series, namely, beta,beta'-tetramethylhexadecanedioic acid (M16betabeta) and gamma,gamma'-tetramethyloctadocanedioic acid (M18gammagamma) as well as HNF-4alpha 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-4alpha ligand antagonists and by HNF-4alpha siRNA was accounted for by suppression of HNF-4alpha transcription and protein expression. alpha,alpha'-tetrachlorotetradecanedioic acid (Cl-DICA), a MEDICA analogue that fails to suppress HNF-4alpha, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF-4alpha converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNF-4alpha activity by natural or xenobiotic HNF-4alpha ligand antagonists or by HNF-4alpha siRNA may offer a treatment mode for CRC.
肝细胞核因子-4α（HNF-4α）是脂肪酸营养素和外源性两亲性羧酸盐的作用靶点，可能是膳食脂肪酸对结直肠癌（CRC）产生不同影响的原因。通过评估HNF-4α拮抗剂和HNF-4α siRNA对培养的CRC细胞生长和增殖的影响以及对体内异种移植裸鼠的影响，验证了HNF-4α在CRC中假定的作用。MEDICA系列的HNF-4α配体拮抗剂，即β，β'-四甲基十六烷二酸（M16ββ）和γ，γ'-四甲基十八烷二酸（M18γγ）以及HNF-4α siRNA在此显示可抑制HT29和Caco2 CRC细胞的生长和增殖，同时伴有亚G1期细胞群体增加、PCNA下调、caspase-3激活、Bak上调和细胞质细胞色素c上调以及Bcl-2下调，导致凋亡死亡。在用HT29 CRC细胞异种移植的裸鼠中进一步证实了CRC生长的抑制与凋亡同时发生。HNF-4α配体拮抗剂和HNF-4α siRNA对CRC的抑制作用是通过抑制HNF-4α转录和蛋白质表达来实现的。α，α'-四氯十四烷二酸（Cl-DICA）是一种不能抑制HNF-4α的MEDICA类似物，在抑制培养的或异种移植的HT29 CRC细胞生长方面无效。因此，HNF-4α转录活性增加并作用于编码抗凋亡癌基因和细胞因子的基因可能促进CRC的发展。天然或外源性HNF-4α配体拮抗剂或HNF-4α siRNA对HNF-4α活性的抑制可能为CRC提供一种治疗模式。
