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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 up-regulated 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.

SUBMITTER: DeZwaan-McCabe D

PROVIDER: S-EPMC3868529 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis.

DeZwaan-McCabe Diane D Riordan Jesse D JD Arensdorf Angela M AM Icardi Michael S MS Dupuy Adam J AJ Rutkowski D Thomas DT

PLoS genetics 20131219 12

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 up-regulated ...[more]

PMID: 24367269

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Project description:AimTo investigate the effects of blueberry on hepatic fibrosis and NF-E2-related factor 2 (Nrf2) transcription factor in rats.MethodsForty-five male Sprague-Dawley rats were randomly divided into control group (A); CCl(4)-induced hepatic fibrosis group (B); blueberry prevention group (C); Dan-shao-hua-xian capsule (DSHX) prevention group (D); and blueberry + DSHX prevention group (E). Liver fibrosis was induced in rats by subcutaneous injection of CCl(4) and a high-lipid/low-protein diet for 8 wk (except the control group). The level of hyaluronic acid (HA) and alanine aminotransferase (ALT) in serum was examined. The activity of superoxide dismutase (SOD), glutathione-S-transferase (GST) and malondialdehyde (MDA) in liver homogenates was determined. The degree of hepatic fibrosis was evaluated by hematoxylin and eosin and Masson staining. Expression of Nrf2 and NADPH quinone oxidoreductase 1 (Nqo1) was detected by real-time reversed transcribed-polymerase chain reaction, immunohistochemical techniques, and western blotting.ResultsCompared with group B, liver indices, levels of serum HA and ALT of groups C, D and E were reduced (liver indices: 0.038 +/- 0.008, 0.036 +/- 0.007, 0.036 +/- 0.005 vs 0.054 +/- 0.009, P < 0.05; HA: 502.33 +/- 110.57 ng/mL, 524.25 +/- 255.42 ng/mL, 499.25 +/- 198.10 ng/mL vs 828.50 +/- 237.83 ng/mL, P < 0.05; ALT: 149.44 +/- 16.51 U/L, 136.88 +/- 10.07 U/L, 127.38 +/- 11.03 U/L vs 203.25 +/- 31.62 U/L, P < 0.05), and SOD level was significantly higher, but MDA level was lower, in liver homogenates (SOD: 1.36 +/- 0.09 U/mg, 1.42 +/- 0.13 U/mg, 1.50 +/- 0.15 U/mg vs 1.08 +/- 0.19 U/mg, P < 0.05; MDA: 0.294 +/- 0.026 nmol/mg, 0.285 +/- 0.025 nmol/mg, 0.284 +/- 0.028 nmol/mg vs 0.335 +/- 0.056 nmol/mg, P < 0.05). Meanwhile, the stage of hepatic fibrosis was significantly weakened (P < 0.05). Compared with group A, the activity of GST liver homogenates and expression levels of Nrf2 and Nqo1 in group B were elevated (P < 0.05). The expression level of Nrf2 and Nqo1 in groups C, D, and E were increased as compared with group B, but the difference was not significant.ConclusionBlueberry has preventive and protective effects on CCl(4)-induced hepatic fibrosis by reducing hepatocyte injury and lipid peroxidation. However, these effects may not be related to the activation of Nrf2 during long-term of CCl(4).

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The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis.

Publications

The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis.

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