Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Schwartz, Betty; Algamas-Dimantov, Anna; Hertz, Rachel; Nataf, Jennifer; Kerman, Ayelet; Peri, Irena; Bar‐Tana, Jacob

doi:10.1002/ijc.24041

Cited by 46 publications

(53 citation statements)

References 32 publications

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“…These cells have been used for the intestinal expression of gluconeogenic enzymes, G6Pase and PEPCK, and that of related transcription factors, HNF1α and HNF4α (5,9,18,24,35). When stimulated with dcAMP/ Dex, the gene expression of G6Pase and PEPCK was up-regulated (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…This might result in a change in the homeostasis of fat metabolism, which should be examined in future studies. EGCG is also a candidate for a chemopreventive agent, since HNF4α was proposed as a target for the inhibition of colorectal cancer (24). Intestinal G6Pase might be involved in the ab- The results were normalized using the level of β-actin, and are expressed as the mean ± SE relative to that for dcAMP/ Dex-stimulated cells (100%) from 3 determinations.…”

Section: Referencesmentioning

confidence: 99%

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Effects of (-)-epigallocatechin-3-O-gallate on expression of gluconeogenesisrelated genes in the mouse duodenum

Yasui¹,

Tanabe

Miyoshi

et al. 2011

Biomed. Res.

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Green tea has been shown to have many beneficial health effects. We have previously reported that dietary (−)-epigallocatechin-3-O-gallate (EGCG), the major polyphenol in green tea, reduced gene expressions of gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), in the normal mouse liver. In the present study, we examined the effects of intragastrical administration of EGCG on the expression of gluconeogenesis-related genes in the mouse intestine. The results of experiments with the semi-quantitative reverse transcription-polymerase chain reaction indicated that EGCG at 0.6 mg/head caused a reduced expression of G6Pase, PEPCK, hepatocyte nuclear factor 1α (HNF1α), and HNF4α. Experiments using the quantitative real-time polymerase chain reaction confirmed these effects. We then examined the effects of EGCG using human colon carcinoma Caco-2 cells stimulated with dexamethasone and dibutyryl cAMP. The results were generally consistent with those from the experiments in vivo. The present findings suggest EGCG to contribute to the beneficial effects of green tea on diabetes, obesity, and cancer by modulating gene expression in the intestine.

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Section: Discussionmentioning

confidence: 99%

Section: Referencesmentioning

confidence: 99%

Effects of (-)-epigallocatechin-3-O-gallate on expression of gluconeogenesisrelated genes in the mouse duodenum

Yasui¹,

Tanabe

Miyoshi

et al. 2011

Biomed. Res.

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“…The expression of these promoters varies in different tissues; only the small and large intestine tissues express these two types of promoters (24). It is known that HNF-4α play an important role in the development and normal functioning of the intestine, at the level of epithelial morphology and differentiation (25), cell junction assembly and adhesion (26) and cell proliferation (27). There are also evidences for the association between HNF-4α and colorectal cancer (24,27).…”

Section: Immunohistochemical Analyses Of Hnf-4α and Their Controlled mentioning

confidence: 99%

“…It is known that HNF-4α play an important role in the development and normal functioning of the intestine, at the level of epithelial morphology and differentiation (25), cell junction assembly and adhesion (26) and cell proliferation (27). There are also evidences for the association between HNF-4α and colorectal cancer (24,27). The aim of our study was to examine the extent of expression of HNF-4α and proteins controlled by HNF-4α in the intestinal tissue of colorectal cancer and ulcerative colitis patients in order to understand their putative role in the development of colorectal cancer and ulcerative colitis in humans.…”

Section: Immunohistochemical Analyses Of Hnf-4α and Their Controlled mentioning

confidence: 99%

“…Silencing HNF-4α gene expression in HT29 malignant cells by siHNF-4α inhibited the proliferation of these malignant cells. (27 (35) demonstrated that silencing the HNF-4α gene in the intestinal cells followed by the exposure of mice to dextran sodium sulfate (DSS) induced worsened changes in the clinical and pathological symptoms associated with inflammatory bowel disease such as enhanced weight loss, reduced colon length, and altered histological morphology. Their conclusion was that HNF-4α protects against ulcerative colitis caused by exposure to DSS (35).…”

Section: Immunohistochemical Analyses Of Hnf-4α and Their Controlled mentioning

confidence: 99%

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Immunohistochemical analyses of HNF-4α and their controlled proteins in human ulcerative colitis and colorectal cancer tissues

Schwartz

Harari²,

Huszar³

2017

MRAJ

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The gene coding the transcription factor HNF-4α is located on chromosome 20q and is expressed in the liver, pancreas, kidneys, stomach and in the small and large intestine, where it controls important aspects related to morphogenesis and epithelial function. Mucin type MUC4 and MUC2, and β-catenin are representative genes controlled by HNF-4α and expressed in colonic tissue. We used in the present study immunohistochemical analyses to detect different levels of expression of the above mentioned proteins in colonic tissues of colorectal cancer and ulcerative colitis patients. We demonstrate high expression levels of HNF-4α in normal colon tissue, however, in adenoma, HNF-4α levels of expression decreased and in carcinoma of the large intestine; the levels were very low or invisible. Similarly, in ulcerative colitis patients the expression HNF-4α levels of the protein were significantly lower than the control group. Expression levels of MUC2 and MUC4 levels were significantly lower in the adenocarcinoma and ulcerative colitis groups than in the control group. In contrast, the expression level of β-catenin increased and changed from a membrane to a nuclear localization in the adenocarcinoma group only. We surmise that HNF-4α plays an important role in prevention of ulcerative colitis and colorectal cancer in humans. As a result, altered expression of the proteins MUC2 and MUC4 controlled by HNF-4α indicate that the defensive role attributed to them is not properly performed. In contrast, the Wnt / β-catenin pathway controlled by HNF-4α becomes active in samples from the stage of the adenoma and reached its peak in the carcinoma samples.

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A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets

Grade

Hummon

Camps

et al. 2010

Intl Journal of Cancer

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Genes that are highly overexpressed in tumor cells can be required for tumor cell survival and have the potential to be selective therapeutic targets. In an attempt to identify such targets, we combined a functional genomics and a systems biology approach to assess the consequences of RNAi-mediated silencing of overexpressed genes that were selected from 140 gene expression profiles from colorectal cancers (CRCs) and matched normal mucosa. In order to identify credible models for in-depth functional analysis, we first confirmed the overexpression of these genes in 25 different CRC cell lines. We then identified five candidate genes that profoundly reduced the viability of CRC cell lines when silenced with either siRNAs or short-hairpin RNAs (shRNAs), i.e., HMGA1, TACSTD2, RRM2, RPS2 and NOL5A. These genes were further studied by systematic analysis of comprehensive gene expression profiles generated following siRNA-mediated silencing. Exploration of these RNAispecific gene expression signatures allowed the identification of the functional space in which the five genes operate and showed enrichment for cancer-specific signaling pathways, some known to be involved in CRC. By comparing the expression of the RNAi signature genes with their respective expression levels in an independent set of primary rectal carcinomas, we could recapitulate these defined RNAi signatures, therefore, establishing the biological relevance of our observations. This strategy identified the signaling pathways that are affected by the prominent oncogenes HMGA1 and TACSTD2, established a yet unknown link between RRM2 and PLK1 and identified RPS2 and NOL5A as promising potential therapeutic targets in CRC.The application of parallel gene expression profiling techniques to large sets of primary tumor samples has revealed profound alterations in the cancer transcriptome. The catalogs of deregulated genes defined by such approaches are not only important because they provide new insight into tumor biology but also because they reveal those genes that are specifically upregulated in tumors, some of which may represent promising new antitumor molecular targets.Finding such critical genes within a complex expression signature, however, remains a formidable challenge. One possible approach to this problem is to modulate the expression of these genes in cell line models. For example, loss-of-function (LOF) analysis can be used to identify genes whose reduction of expression may have a direct impact on cancer cell survival.We recently presented comprehensive gene expression signatures of colorectal cancer (CRC) and matched normal mucosa.1,2 In order to identify those genes that could directly influence tumor survival and thus, may represent candidate molecular targets, we first identified CRC cell lines in which the expression of these genes was upregulated accordingly. We then used RNAi-mediated gene silencing to reduce their expression and quantified cell survival. To uncover their roles in cell viability, we monitored genome-wide transcriptional c...

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Inhibition of colorectal cancer by targeting hepatocyte nuclear factor‐4α

Cited by 46 publications

References 32 publications

Effects of (-)-epigallocatechin-3-O-gallate on expression of gluconeogenesisrelated genes in the mouse duodenum

Effects of (-)-epigallocatechin-3-O-gallate on expression of gluconeogenesisrelated genes in the mouse duodenum

Immunohistochemical analyses of HNF-4α and their controlled proteins in human ulcerative colitis and colorectal cancer tissues

A genomic strategy for the functional validation of colorectal cancer genes identifies potential therapeutic targets

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