Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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. 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.

ORGANISM(S): Mus musculus

SUBMITTER: David Rutkowski

PROVIDER: E-GEOD-51188 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Hepatocellular carcinoma (HCC) is a prevalent human cancer with rising incidence worldwide. Human HCC is frequently associated with chronic liver inflammation and cirrhosis, pathophysiological processes that are a consequence of chronic viral infection, disturbances in metabolism, or exposure to chemical toxicants. To better characterize the pathogenesis of HCC, we used a human disease-relevant mouse model of fibrosis-associated hepatocarcinogenesis. In this model, marked liver tumor response caused by a pro-mutagenic chemical N-nitrosodiethylamine in presence of liver fibrosis was associated with epigenetic events indicative of genomic instability. Therefore, we hypothesized that DNA copy number alterations (CNAs), a feature of genomic instability and a common characteristic of cancer, are concordant between human HCC and mouse models of fibrosis-associated hepatocarcinogenesis. We evaluated DNA CNAs and changes in gene expression in the mouse liver (normal, tumor and non-tumor cirrhotic tissues). In addition, we compared our findings to those in human HCC (tumor and non-tumor cirrhotic/fibrotic tissues). We observed that while fibrotic liver tissue is largely devoid of DNA CNAs, highly frequently occurring DNA CNAs are found in mouse tumors, which is indicative of a profound increase in chromosomal instability in HCC. When compared to CNAs in human HCC, we found that 33% of genes in these segments are similarly affected in the mouse tumors. Our results suggest that CNAs most commonly arise in neoplastic tissue rather than in fibrotic liver, and demonstrate the utility of this mouse model in replicating the molecular features of human HCC. Genomic DNA was extracted from frozen liver samples from vehicle-control and DEN+CCl4-treated mice using a DNEasy kit (Qiagen, Valencia, CA). Eighteen mouse tumor samples were included in the study, as well as 18 matched non-tumor samples taken from fibrotic, non-tumorous, surrounding liver tissue from the same mice. Liver DNA from 6 vehicle control-mice was pooled and used as the reference genome in the aCGH experiments. Copy number alterations were identified using the normalized data.

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

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