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The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

ABSTRACT: Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is upregulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE51188 | GEO | 2013/09/27

SECONDARY ACCESSION(S): PRJNA221566

REPOSITORIES: GEO

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The Stress-Regulated Transcription Factor CHOP Promotes Hepatic Inflammatory Gene Expression, Fibrosis, and Oncogenesis

Project description:Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is upregulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases. 24 samples were analyzed from 9 month old male C57BL/6J or backcrossed Chop-/- male mice, injected with either PBS or a single dose of 25 mg/kg diethylnitrosamine (DEN) at 15 d.o. Samples are either from whole liver or liver tumors.

2013-09-27 | E-GEOD-51188 | biostudies-arrayexpress

Microarray to find CHOP dependent genes in response to proteasome inhibition

Project description:Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression of global protein synthesis coincident with preferential translation of ATF4, a transcriptional activator of the Integrated stress response (ISR). Depending on the extent of protein disruption, ATF4 may not be able to restore proteostatic control and instead switch to a terminal outcome that features elevated expression of the transcription factor CHOP (GADD153/DDIT3). The focus of this study was to define the mechanisms by which CHOP directs gene regulatory networks that determine cell fate. We find that in response to proteasome inhibition, CHOP induces the expression of a collection of genes encoding transcription regulators, including ATF5, which is preferentially translated during eIF2 phosphorylation. Transcriptional expression of ATF5 is directly activated by both CHOP and ATF4. Knock-down of ATF5 increased cell survival in response to proteasome inhibition, supporting the idea that both ATF5 and CHOP have pro-apoptotic functions. Transcriptome analyses of ATF5-dependent genes revealed targets involved in apoptosis, including, NOXA, which is important for inducing cell death during proteasome inhibition. This study suggests that the ISR features a feed-forward loop of stress induced transcriptional regulators, each subject to transcriptional and translational control that can switch cell fate towards apoptosis. 8 plates (10cm) of WT and and 8 plates (10cm) of CHOP-/- MEF cells were subject to no stress (4 each for a total of 8) or treated for 8 hours with 1uM MG132 (4 each for a total of 8). Unstressed cells were harvested at the same time as the stressed cells

2013-09-05 | E-GEOD-43713 | biostudies-arrayexpress

Microarray to find CHOP dependent genes in response to proteasome inhibition

2013-09-05 | GSE43713 | GEO

mRNAseq and proteomic data set of one week old WT (Chop wt/wt CkmmCre wt/wt Dars2 fl/fl), Chop KO (Chop ko/ko CkmmCre wt/wt Dars2 fl/fl), Dars2 KO (Chop wt/wt CkmmCre tg/wt Dars2 fl/fl) and DKO (Chop ko/ko CkmmCre tg/wt Dars2 fl/fl) mice

Project description:Maintenance of mitochondrial homeostasis is essential for a broad spectrum of signalling, metabolic and energetic processes. Consequently, mitochondrial dysfunction is linked to the development of a wide range of myopathies and many common diseases including type 2 diabetes, Parkinson’s and Alzheimer’s diseases. In response to disturbed mitochondrial proteostasis, an organelle-specific stress response is initiated, which results in a global adaptive transcriptional response partially sharing the signature of the integrated stress response (ISR). However, the exact sequence of events of the signalling cascade resulting in the activation of the ISR remains elusive. CHOP was the first transcription factor (TF) proposed to play a role in this process, although - due to the lack of a trans-activating domain - it needs to heterodimerize with other TFs to activate or suppresses its target genes. Therefore, we decided to investigate the molecular aspects and in vivo functions of CHOP in a murine model of mitochondrial dysfunction triggered by the loss of mitochondrial translation. Disruption of mitochondrial translation by heart and skeletal muscle-specific knock-out of the mitochondrial aspartyl-tRNA synthetase DARS2 on its own results in death of the animals within 7-8 weeks. Additional deletion of CHOP even further reduces the lifespan to less than 3 weeks, suggesting an existential role of the TF within the initiated stress signalling pathway. Our recent data indicates that CHOP's impact arises from the regulation of another TF with detrimental effects when exceedingly activated under certain circumstances: ATF4.

2022-04-04 | GSE149010 | GEO

RNA-seq in livers of wild-type (WT) controls, PiZ and PIZ mice deleted for Chop (PiZ/Chop-/-)

Project description:Transgenic PiZ mice have been genetically engineered to express ATZ and have been a valuable experimental model for liver disease due to AAT polymerization. ATZ accumulates in these mice within the endoplamic reticulum (ER) of hepatocytes in a nearly identical manner to livers of affected patients. To investigate the role of the transcription factor CHOP in the pathogenesis of liver damage induced by ATZ, we performed RNA-seq in livers of 6-week-old wild type, PiZ and PiZ mice deleted for Chop. All groups were matched for the strain, age, and the gender.

2020-12-01 | GSE118290 | GEO

Regulation and role of the pro-apoptotic transcription factor CHOP in Idiopathic Pulmonary Fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease characterized by alveolar epithelial cell type II (AECII) injury and enhanced fibroblast/myofibroblast proliferation. Recent data show that maladaptive endoplasmic reticulum (ER)-stress leading to AECII apoptosis could play a key role in IPF, although it is still unclear how precisely such response is initiated and signalled. C/EBP homologous protein (CHOP) has been suggested to contribute to a maladaptive ER-stress response in general and has been found to be induced and to be translocated into the nucleus of AECII in IPF in particular. We here show for the first time a novel mechanism for the regulation of CHOP expression during ER-stress in AECII via AP-1 and c-Ets-1. We found these two transcription factors to be up-regulated in AECII under ER-stress conditions and to interact with each other to jointly bind to the CHOP promoter, thereby inducing CHOP gene expression. Moreover, we show for the first time that singular CHOP overexpression in vitro and in vivo is indeed capable of inducing apoptosis of AECII and, consequently, lung fibroblast proliferation and up-regulation of pro-fibrotic markers. We therefore believe that CHOP plays a key role in AEC injury and consecutive fibrosis.

2017-09-23 | GSE87298 | GEO

Longitudinal Study of Transcriptomic Changes Occurring Over the Course of CHOP Treatment in Canine Lymphoma

Project description:The standard treatment for canine lymphoma (cL) is the CHOP chemotherapy protocol. Most cL patients treated with CHOP initially achieve remission but the duration varies and the majority of dogs eventually relapse with a multidrug resistant phenotype. This study assesses changes in gene expression occurring in cL tumor cell populations over the course of CHOP treatment. We measured gene expression using RNA-Seq on 15 cL patient samples taken prior to treatment and again 6 weeks into treatment.

2021-07-14 | GSE179920 | GEO

Gene expression profile of wild type, PiZ and PiZ/Chop-/- mouse livers at two different ages

Project description:To investigate the role of CHOP in the pathogenesis of liver disease due to Z alpha-1 antitrypsin in juvenile and older mice, we performed Quant-seq experiments at 6 and 36 weeks of age in wild type, PiZ and PiZ/Chop-/- mouse livers

2020-08-13 | GSE141593 | GEO

RNA sequencing (RNA-SEQ) of 21 HBV-HCC patients with non-neoplastic liver and tumor tissues

Project description:Purpose: Chronic Hepatitis B virus (HBV) infection leads to liver fibrosis which is a major risk factor in Hepatocellular carcinoma (HCC) and an independent risk factor of recurrence after HCC tumor resection. HBV genome can be inserted into human genome, and chronic inflammation may trigger somatic mutations. Several studies characterized HBV integration sites in HCC patients with regard to frequently occurring hotspots. However, how HBV integration and other genomic changes contribute to the risk of tumor recurrence with regard to different degree of liver fibrosis is not clearly understood. In this study, we aim to find potential molecular mechanisms underlying tumor recurrence of HBV-associated HCC (HBV-HCC) with different degree of liver fibrosis. Methods: We performed RNA sequencing of 21 pairs of tumor and non-neoplastic liver tissues of HBV-HCC patients and performed comprehensive genomic analysis of our RNAseq data and public available sequencing data related to HBV-HCC. We developed a robust pipeline for sensitively identifying HBV integration sites based on sequencing data. Simulations with sequencing data showed that our method outperformed existing methods. We also compared SNPs of each sample with SNPs in cancer census database and inferred patient’s pathogenic SNP loads in tumor and non-neoplastic liver tissues. Conclusions: The HBV-integration and pathogenic SNP load patterns for HCC recurrence risk vary depending on liver fibrosis stage, suggesting potentially different tumorigenesis mechanisms for low and high liver fibrosis patients.

2018-03-01 | GSE94660 | GEO

Epigenetic signatures of alcohol abuse and hepatitis infection during hepatocarcinogenesis

Project description:Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Altered DNA methylation landscapes are ubiquitous features of cancer. Interpretation of epigenetic aberrations in HCC is confounded by effects of multiple etiologic drivers and underlying cirrhosis in most cases. We globally profiled the DNA methylome of 34 normal livers and 122 primary liver disease tissues arising in the setting of chronic hepatitis B (HBV) or C (HCV) viral infection, alcoholism (EtOH), and other causes to examine how these environmental agents impact DNA methylation in a manner that contributes to liver disease. Our results demonstrate that each etiologic factor leaves unique and overlapping signatures on the DNA methylome. CpGs aberrantly methylated in cirrhosis-HCV and conserved in HCC were enriched for cancer driver genes, suggesting a pathogenic role for HCV-induced methylation changes. Additionally, large genomic regions displaying stepwise hypermethylation or hypomethylation during disease progression were identified. HCC-HCV/EtOH methylomes overlap highly with cryptogenic HCC, suggesting shared epigenetically deregulated pathways for hepatic carcinogenesis. Finally, overlapping methylation abnormalities between primary and cultured tumors unveil highly conserved epigenetic signatures in HCC. Taken together, this study characterizes progressive liver DNA methylome changes under exposure to detrimental environmental agents and illuminates possible biomarkers for early detection of HCC. 156 primary tissues and 25 cultured normal and HCC cell lines

2014-09-16 | E-GEOD-60753 | biostudies-arrayexpress

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