Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Meng, Yan; Li, Shengnan; Anjum, Khalid Mahmood; Gui, Long-Xin; Zhu, Shanshan; Li, Jun; Chen, Jiakun; Li, Qingfeng; Ye, Guodong; Wang, Wenjie; Wu, Jiafa; Cai, Wangyu; Sun, Guangbin; Liu, Yunjia; Liu, Rongfu; Zhang, Zhiming; Li, Boan

doi:10.1242/jcs.135053

Cited by 62 publications

(66 citation statements)

References 48 publications

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“…Interestingly, a higher level of HNF4α was also associated with a lower level of Axin2 , a positive target of β‐catenin (Figure F). This corroborates previous studies performed by our laboratory and others suggesting that HNF4α could impair β‐catenin signalling . Altogether, these data suggest that loss of HNF4α in pretumoural hepatocytes with β‐catenin activation could play a part during hepatocarcinogenesis.…”

Section: Resultssupporting

confidence: 92%

“…Populations of small cells were more prominent around the portal vein and also mostly proliferative (Figure B). Although HNF4α deficiency was described to cause epithelial‐mesenchymal transition (EMT), E‐cadherin was normally membrane localized in hepatocytes lining the disorganized portal triads (Figure B). There was also no impact of Hnf4a disruption on the zonal pattern of E‐cadherin in the liver lobule (Figure B‐C), or on Cdh1 mRNA level (Figure D).…”

Section: Resultsmentioning

confidence: 99%

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The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

Sartor

Bachelot

Lager

et al. 2019

Liver International

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Background & Aims Loss of hepatocyte nuclear factor‐4α (HNF4α), a critical factor driving liver development and differentiation, is frequently associated with hepatocellular carcinoma (HCC). Our recent data revealed that HNF4α level was decreased in mouse and human HCCs with activated β‐catenin signalling. In addition, increasing HNF4α level by miR‐34a inhibition slowed tumour progression of β‐catenin‐activated HCC in mice. Methods We generated a Hnf4aflox/flox/Apcflox/flox/TTR‐CreERT2 (Hnf4a/Apc∆Hep) mouse line and evaluated the impact of Hnf4a disruption on HCC development and liver homoeostasis. Results There was no significant impact of Hnf4a disruption on tumour onset and progression in Apc∆Hep model. However, we observed an unexpected phenotype in 28% of Hnf4a∆Hep mice maintained in a conventional animal facility, which presented disorganized portal triads, characterized by stenosis of the portal vein and increased number and size of hepatic arteries and bile ducts. These abnormal portal structures resemble the human idiopathic non‐cirrhotic portal hypertension syndrome. We correlated the presence of portal remodelling with a higher expression of protein and mRNA levels of TGFβ and BMP7, a key regulator of the TGFβ‐dependent endothelial‐to‐mesenchymal transition. Conclusion These data demonstrate that HNF4α does not play a major role during β‐catenin‐driven HCC, thus revealing that the tumour suppressor role of HNF4α is far more complex and dependent probably on its temporal expression and tumour context. However, HNF4α loss in adult hepatocytes could induce abnormal portal structures resembling the human idiopathic non‐cirrhotic portal hypertension syndrome, which may result from endothelial‐ and epithelial‐to‐mesenchymal transitions.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

Sartor

Bachelot

Lager

et al. 2019

Liver International

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“…All seven TFs are involved in normal liver development and physiology 75–80 , with CEBPB, RXRA and MAF TFs also involved with inflammation and cellular stress 81–87 . The most strongly perturbed FOXA1/2 and HNF4A TFs have also been implicated in WNT signaling pathways that promote carcinogenesis and epithelial-to-mesenchymal (EMT) transition 88–91 , which links the DNA methylation changes to the risk of neoplastic progression.…”

Section: Resultsmentioning

confidence: 99%

A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets

Wijetunga¹,

Pascual²,

Tozour³

et al. 2016

Oncogene

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The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumors is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events. We find the HCV-infected liver to have a pattern of acquisition of DNA methylation targeted to candidate enhancers active in liver cells, enriched for the binding sites of the FOXA1, FOXA2 and HNF4A transcription factors. These enhancers can be subdivided into those proximal to genes implicated in liver cancer or to genes involved in stem cell development, the latter distinguished by increased CG dinucleotide density and polycomb-mediated repression, manifested by the additional acquisition of histone H3 lysine 27 trimethylation (H3K27me3). Transcriptional studies on our samples showed that the increased DNA methylation at enhancers was associated with decreased local gene expression, results validated in independent samples from The Cancer Genome Atlas (TCGA). Pharmacological depletion of H3K27me3 using the EZH2 inhibitor GSK343 in HepG2 cells suppressed cell growth and also revealed that local acquired DNA methylation was not dependent upon the presence of polycomb-mediated repression. The results support a model of HCV infection influencing the binding of transcription factors to cognate sites in the genome, with consequent local acquisition of DNA methylation, and the added repressive influence of polycomb at a subset of CG-dense cis-regulatory sequences. These epigenetic events occur before neoplastic transformation, resulting in what may be a pharmacologically-reversible epigenetic field defect in HCV-infected liver.

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“…90 While in rat livers HNF4α protected development of liver cancer through inhibition of β-catenin signalling, 89 it appears that in mouse livers HNF4α represses tumor through inhibition of both β-catenin and c-myc expression. 91,92 In the liver, HNF4α is under control of several pathways alterations of which might reduce levels of HNF4α and cause liver cancer. One of these pathways is Hippo signaling.…”

Section: Liver-specific Tumor Suppressor Protein Hnf4αmentioning

confidence: 99%

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

Timchenko

Lewis²

2014

Cancer Stud Mol Med Open J

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Liver cancer is one of the most lethal cancers. Quiescent liver expresses up to 20 tumor suppressor proteins including Rb, p53, CCAAT-Enhancer-Binding Protein (C/EBP)α, Hepatocyte Nuclear Factor (HNF4)α and p16 and it is well protected from development of liver cancer. However, the negative control of liver proliferation by these factors and other tumor suppressor genes is eliminated in liver cancer. Studies of liver regeneration after surgery and injury have provided fundamental mechanisms on how liver neutralizes tumor suppressor proteins for the time of regeneration; however, studies of liver cancer in animal models and in human samples showed several additional pathways of this neutralization. One of these additional pathways includes activation of a small subunit of the proteasome, Gankyrin. Gankyrin is dramatically increased in human hepatocellular carcinoma (HCC) and in animal models of carcinogenesis. Once activated Gankyrin triggers degradation of main tumor suppressor proteins during development of liver cancer using slightly different mechanisms. Recent studies identified mechanisms which repress Gankyrin in quiescent livers and mechanisms of activation of Gankyrin in liver cancer. These mechanisms involve a communication between Farnesoid X Receptor (FXR) signaling and chromatin remodelling proteins mediated by members of C/EBP family. It has been recently shown that C/EBPα plays a critical role in this network and that the activation of C/EBPα in cirrhotic livers with HCC inhibits cancer progression. This C/EBPα-dependent inhibition of liver cancer involves activation of a majority of tumor suppressor genes and repression of tumor initiating pathways such as β-catenin and c-myc. These recent findings provide a background for FXR-based and C/EBPα-based approaches to treat liver cancer.

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Double-negative feedback loop between Wnt/β-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma

Cited by 62 publications

References 48 publications

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

The concomitant loss of APC and HNF4α in adult hepatocytes does not contribute to hepatocarcinogenesis driven by β‐catenin activation

A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

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