No abstract

Hepatocyte nuclear factor‐4α (HNF‐4α) 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‐4α in CRC has been verified here by evaluating the effect of HNF‐4α antagonists and HNF‐4α siRNA on CRC growth and proliferation in cultured CRC cells and xenotransplanted nude mice in vivo. HNF‐4α ligand antagonists of the MEDICA series, namely, β,β'‐tetramethylhexadecanedioic acid (M16ββ) and γ,γ'‐tetramethyloctadocanedioic acid (M18γγ) as well as HNF‐4α 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‐4α ligand antagonists and by HNF‐4α siRNA was accounted for by suppression of HNF‐4α transcription and protein expression. α,α'‐tetrachlorotetradecanedioic acid (Cl‐DICA), a MEDICA analogue that fails to suppress HNF‐4α, was ineffective in suppressing growth of cultured or xenotransplanted HT29 CRC cells. Hence, increased transcriptional activity of HNF‐4α converging onto genes coding for antiapoptotic oncogenes and cytokines may promote CRC development. Suppression of HNF‐4α activity by natural or xenobiotic HNF‐4α ligand antagonists or by HNF‐4α siRNA may offer a treatment mode for CRC. © 2008 Wiley‐Liss, Inc.

This article is available online at http://www.jlr.org stationary, pluripotent stem cells at the base of the crypt give rise to rapidly proliferating cells that differentiate into postmitotic columnar absorptive colonocytes, mucinsecreting goblet cells, and enteroendocrine cells as they migrate from the crypt base to the surface, followed fi nally by their shedding into the intestinal lumen (reviewed in Ref. 1 ). Several signaling pathways, notably ␤ -catenin/Tcf and hepatocyte nuclear factor (HNF)-4 ␣ , modulate and control the proliferation and differentiation of adult colonocytes, whereas their perturbation via mutation or epigenetic modifi cation may ultimately result in colorectal cancer (CRC). Moreover, cell dedifferentiation correlates with key tumor features, such as tumor progression rates, invasiveness, drug resistance, and metastatic potential ( 2 ). Hence, perturbation of programming commitment during ontogenesis may mimic primary features of intestinal oncogenesis. In contrast to humans, major intestinal maturation processes of rodents take place only following birth ( 3 ), allowing for searching intestinal ontogenesis as a function of variable conditions reported to promote or suppress CRC.The metabolic syndrome (MetS) and its individual diseases (upper-body obesity, type 2 diabetes, dyslipidemia, and hypertension) are associated with an increased risk for CRC, and CRC incidence seems to be associated with the number of MetS components present at baseline (reviewed in Refs. 4, 5 ). Thus, the relative risk (RR) of CRC increases 2-fold with increase in waist circumference of MetS subjects ( 6 ), whereas the age-and sex-adjusted RR of CRC for an hemoglobin (Hb)A1c у 7% amounts to 2.94, compared with 1. Manuscript received 29 October 2011 and in revised form 20 February 2012. Published, JLR Papers in Press, February 22, 2012 DOI 10.1194 Amelioration of diabesity-induced colorectal ontogenesis by omega-3 fatty acids in mice Abbreviations: CRC, colorectal cancer; EPA, eicosapentaenoic acid; HE, hematoxylin and eosin; HNF-4 ␣ , hepatocyte nuclear factor 4 ␣ ; LA, linoleic acid; LBD, ligand binding domain; LCFA, long-chain fatty acid; MetS, metabolic syndrome; PCNA, proliferating cell nuclear antigen; RR, relative risk.

HNF-4α transcriptional expression and activity are tightly controlled by epigenetic mechanisms. HDAC inhibitor targeting of HNF-4α may serve as an effective treatment for advanced colon carcinomas, since downstream cancer-associated target genes such as MUC4 are significantly down-regulated by this treatment.

The global obesity / diabetes epidemic has resulted in robust increase in the incidence of colorectal cancer (CRC). Epidemiological, animal and human studies have indicated efficacy of (n-3) PUFA in chemoprevention of sporadic and genetic-driven CRC. However, diabetes-promoted CRC presents a treatment challenge that surpasses that of sporadic CRC. This report analyzes the efficacy of (n-3) PUFA generated by the fat-1 transgene that encodes an (n-6) to (n-3) PUFA desaturase, and of synthetic (n-3) PUFA mimetic (MEDICA analog), to suppress CRC development in carcinogen-induced diabetes-promoted animal model. Carcinogen-induced CRC is shown here to be promoted by the diabetes context, in terms of increased aberrant crypt foci (ACF) load, cell proliferation and epithelial dedifferentiation, being accompanied by increase in the expression of HNF4α, β-catenin, and β-catenin-responsive genes. Incorporating the fat-1 transgene in the diabetes context, or oral MEDICA treatment, resulted in ameliorating the diabetic phenotype and in abrogating CRC, with decrease in ACF load, cell proliferation and the expression of HNF-4α, β-catenin, and β-catenin-responsive genes. The specificity of (n-3) PUFA in abrogating CRC development, as contrasted with enhancing CRC by (n-6) PUFA, was similarly verified in CRC cell lines. These findings may indicate prospective therapeutic potential of (n-3) PUFA or MEDICA in the management of CRC, in particular diabetes-promoted CRC.