An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis

Hatziapostolou, Maria; Polytarchou, Christos; Aggelidou, Eleni; Drakaki, Alexandra; Poultsides, George A.; Jaeger, Savina; Ogata, Hisanobu; Karin, Michael; Struhl, Kevin; Hadzopoulou-Cladaras, Margarita; Iliopoulos, Dimitrios

doi:10.1016/j.cell.2011.10.043

Cited by 415 publications

(315 citation statements)

References 47 publications

(59 reference statements)

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“…4A). Wound healing was another common category, consistent with HNF4␣ playing a role in protecting the colonic epithelium from inflammatory bowel disease (10,11,13,27,78). In contrast, HNF4␣2 specifically upregulated genes involved in cell death and response to extracellular stimuli, while the only category of genes upregulated only by HNF4␣8 was cell adhesion, although several of those genes actually promote cell growth (Fig.…”

Section: Generation and Characterization Of Isoform-specific Hnf4␣-exmentioning

confidence: 70%

“…P1-HNF4␣ acts as a tumor suppressor in the liver (24), inhibiting hepatocyte proliferation and inflammation (25)(26)(27). Several key players in proliferation, including p53, c-Myc, T-cell factor 4 (TCF4 [TCF7L2]), lymphoid enhancer factor 1 (LEF1 [LEF1]), and cyclin D1, have all been shown to physically interact with and antagonize P1-HNF4␣ (12,(28)(29)(30)(31)(32)(33).…”

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confidence: 99%

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Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

Vuong

Chellappa

Dhahbi

et al. 2015

Molecular and Cellular Biology

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The nuclear receptor hepatocyte nuclear factor 4␣ (HNF4␣) is tumor suppressive in the liver but amplified in colon cancer, suggesting that it also might be oncogenic. To investigate whether this discrepancy is due to different HNF4␣ isoforms derived from its two promoters (P1 and P2), we generated Tet-On-inducible human colon cancer ( Thus, the HNF4␣ isoforms play distinct roles in colon cancer, which could be due to differential interactions with the Wnt/␤-catenin/TCF4 and AP-1 pathways.

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Section: Generation and Characterization Of Isoform-specific Hnf4␣-exmentioning

confidence: 70%

mentioning

confidence: 99%

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

Vuong

Chellappa

Dhahbi

et al. 2015

Molecular and Cellular Biology

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“…To further confirm the regulation of HNF4␣ by HBV in cultured primary hepatocytes, we analyzed mRNA expression levels of three specific HNF4␣ target genes, ALDOB, CYP1A2, and G6P, which were previously described to be HNF4␣-specific target genes (62). Cultured primary rat hepatocytes were transfected with the control vector pGEM, pGEMHBV, or the mAKT2 expression plasmid, and the cells were harvested 48 h after transfection.…”

Section: Resultsmentioning

confidence: 99%

“…HNF4␣ expression maintains hepatocyte differentiation, and the loss of HNF4␣ transcriptional activity can lead to the dedifferentiation of hepatocytes and hepatocyte proliferation (36). Inhibition of HNF4␣ can initiate transformation in immortalized hepatocytes through a microRNA (miRNA) inflammatory feedback loop; perturbation of this feedback loop was also found for human hepatocellular carcinoma (62). The loss of HNF4␣ has been directly associated with the development of HCC, and HNF4␣ expression suppressed the development of HCC in a mouse model system (88,89).…”

Section: Discussionmentioning

confidence: 99%

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Rawat

Bouchard

2015

J Virol

107

123

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Chronic infection with hepatitis B virus (HBV) is a risk factor for developing liver diseases such as hepatocellular carcinoma (HCC). HBx is a multifunctional protein encoded by the HBV genome; HBx stimulates HBV replication and is thought to play an important role in the development of HBV-associated HCC. HBx can activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway in some cell lines; however, whether HBx regulates PI3K/AKT signaling in normal hepatocytes has not been evaluated. In studies described here, we assessed HBx activation of PI3K/AKT signaling in an ex vivo model of cultured primary hepatocytes and determined how this HBx activity affects HBV replication. We report that HBx activates AKT in primary hepatocytes and that the activation of AKT decreases HBV replication and HBV mRNA and core protein levels. We show that the transcription factor hepatocyte nuclear factor 4␣ (HNF4␣) is a target of HBx-regulated AKT, and we link HNF4␣ to HBx-regulated AKT modulation of HBV transcription and replication. Although we and others have shown that HBx stimulates and is likely required for HBV replication, we now report that HBx also activates signals that can diminish the overall level of HBV replication. While this may seem counterintuitive, we show that an important effect of HBx activation of AKT is inhibition of apoptosis. Consequently, our studies suggest that HBx balances HBV replication and cell survival by stimulating signaling pathways that enhance hepatocyte survival at the expense of higher levels of HBV replication. IMPORTANCE Chronic hepatitis B virus (HBV) infection is Chronic infection with hepatitis B virus (HBV) remains a major global health problem. Despite the availability of effective HBV vaccines, there are ϳ350 million people worldwide who are chronically infected with HBV. Chronic HBV infection is the major cause of the development of hepatocellular carcinoma (HCC) (1). The level of HBV replication in a chronically HBV-infected individual can vary throughout the course of the infection, and the rise and fall of HBV replication during a chronic infection may affect disease progression (2, 3). There are limited therapeutic options for treating a chronic HBV infection, and the emergence of HBV mutants that are resistant to available therapies is common. Moreover, available anti-HBV drugs typically do not completely eliminate HBV in chronically infected individuals due to the presence and stability of covalently closed circular DNA (cccDNA), a replicative intermediate of HBV that is localized to the nucleus of HBV-infected hepatocytes (4-7). Consequently, there is continued interest in understanding the mechanisms that regulate HBV replication and could serve as potential therapeutic targets.HBV is an enveloped, partially double-stranded DNA virus that belongs to the Hepadnaviridae family of viruses (8). Although HBV is a DNA virus, it replicates through reverse transcription of an RNA intermediate. HBV replication occurs within the viral capsid in the cytosol of hepa...

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“…1A and B) and that miRNA-449a regulates expression of the inflammatory cytokine YKL40 through components of the NOTCH signaling pathway (23). miRNA-125b and miRNA-124, which are downregulated in hepatocarcinoma patients, target IL-6R to modulate the IL-6/ STAT3 pathway and IL-6 production and induce tumorigenicity (46)(47)(48). We demonstrate that expression of miRNA targets IL-6R and JAK1 and that transcription factors PU.1 and STAT3 are upregulated specifically in HCV patients compared to non-HCV patients and healthy individuals (Fig.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

Sarma

Tiriveedhi

Crippin

et al. 2014

J Virol

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Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBP␣, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBP␣, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBP␣. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCEHepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

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An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis

Cited by 415 publications

References 47 publications

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

The Hepatitis B Virus (HBV) HBx Protein Activates AKT To Simultaneously Regulate HBV Replication and Hepatocyte Survival

Hepatitis C Virus-Induced Changes in MicroRNA 107 (miRNA-107) and miRNA-449a Modulate CCL2 by Targeting the Interleukin-6 Receptor Complex in Hepatitis

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