Inhibition of colorectal cancer by targeting hepatocyte nuclear factor-4alpha
Authors: Anna Algamas-Dimantov
Jennifer Nataf
Jacob Bar-Tana
Rachel Hertz
Irena Peri
Betty Schwartz
Ayelet Kerman
Journal: International Journal of Cancer (2009)
Discipline: CLINICAL MEDICINE
Keywords: HNF-4alpha; colorectal cancer; growth inhibition; apoptosis; xenotransplanted
Affiliations: The Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. 

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figure 2. * Red boxes: The HT29 Bcl2, HT29 PCNA, and Caco-2 PCNA blots all appear to look similar to each other.  , 
 Figure 3. * Green boxes: The HNF-4a panels in a) (EtOH M18 treatment) and d) (DMSO TZD treatment) appear to look similar to each other. * Pale orange yellow boxes: The HNF-4a panel in b) looks similar to panels in at least two other, older papers with shared author B. Schwartz, e.g. DOI 10.1677 JME-06-0040 and 10.1002 ijc.23821. Note an upside-down orientation.   , 
 Figure 4. * Pink boxes: Four lanes in the b-actin panel of a) (M18 treatment) look remarkably similar to the b-actin panel in b) (M16 treatment).  , 
 And Figure 5B s b-actin panel also looks similar to three of the four lanes marked in Figure 4 in pink:  , 
 Figure 6B. * Teal boxes: In the Bak panel, lanes Control 1 and 2 look remarkably similar to lanes CI-DICA 1 and 2. * Cyan boxes: In the Cyt-C panel, lanes Control 1 and 2 look remarkably similar to lanes CI-DICA 2 and 3. One might even say they look similar to the lanes marked with the teal boxes.  ,