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.

A Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK)-dependent Transcriptional Program Controls Activation of the Early Growth Response 1 (EGR1) Gene during Amino Acid Limitation

“…In fact, therapies targeting VEGF-A receptor signaling are being employed for the management of aggressive and advanced stage hepatocellular carcinoma (47). Relative to normal mouse liver tissue, diethylnitrosoamine-induced mouse liver tumors have elevated expression of many MEK-and ATF4-dependent AAR target genes, including EGR1 (11.6-fold), ASNS (6.3-fold), cFOS (4.0-fold), and ATF3 (6.6-fold) (48), consistent with the hypothesis that tumors are often nutrient-deprived.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…On the other hand, CHOP promotes hepatic carcinogenesis by enhancing inflammation, fibrosis, and cell death in the liver (DeZwaan-McCabe et al 2013). In addition, Chop −/− mice display smaller tumor nodules with reduced numbers of macrophages and levels of IFNγ.…”

Islet adaptation to obesity and insulin resistance in WNIN/GR-Ob rats

“…18,41 Interestingly, these upregulated genes play a key role in inflammatory diseases of pancreas as well as other organ systems. [42][43][44][45][46][47][48][49][50][51] Some of the notable genes includes Adam17 also known as TNF-a converting enzyme regulates inflammatory cellular processes implicated in renal diseases and metabolic inflammation. 42,43 APOE increases the risk of Alzheimer diseases and is both anti-inflammatory as well as proinflammatory in neuroinflammation.…”

“…47,48 The stress regulated transcription factor DDIT3 promotes hepatic inflammation and fibrosis. 49 NOD2 elevates renal injury by aggravating inflammation and …”