Dataset Information

Loss of estrogen-related receptor ? promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances.

ABSTRACT: Estrogen-related receptor ? (ERR?) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERR? has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERR? in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERR? accelerates the development of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Biochemical and metabolomics studies revealed that loss of ERR? promotes hepatocyte necrosis over apoptosis in response to DEN due to a deficiency in energy production. We further show that increased hepatocyte death and associated compensatory proliferation observed in DEN-injured ERR?-null livers is concomitant with increased nuclear factor ?B (NF-?B)-dependent transcriptional control of cytokine expression in Kupffer cells. In particular, we demonstrate that loss of ERR?-dependent regulation of the NF-?B inhibitor I?B? leads to enhanced NF-?B activity and cytokine gene activation. Our work thus shows that global loss of ERR? activity promotes hepatocellular carcinoma by independent but synergistic mechanisms in hepatocytes and Kupffer cells, implying that pharmacological manipulation of ERR? activity may have a significant clinical impact on carcinogen-induced cancers.

SUBMITTER: Hong EJ

PROVIDER: S-EPMC3816417 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss of estrogen-related receptor α promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances.

Hong Eui-Ju EJ Levasseur Marie-Pier MP Dufour Catherine R CR Perry Marie-Claude MC Giguère Vincent V

Proceedings of the National Academy of Sciences of the United States of America 20131014 44

Estrogen-related receptor α (ERRα) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERRα has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERRα in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERRα accelerates the development of diethylnitrosamine (DEN)-induced hepatocel ...[more]

PMID: 24127579

Similar Datasets

Project description:G-protein-coupled receptor (GPCR)-related proteins are dysregulated and the GPCR CC-chemokine receptor 10 (CCR10) is significantly upregulated in inflammation-driven HCC. However, CCR10's role in inflammation-driven hepatocarcinogenesis remains unknown. The aim of this study was to evaluate the role of CCR10 in inflammation-driven hepatocarcinogenesis. Via a targeted gene expression microarray screening alterations in GPCR family gene expression, we found CCR10 to be significantly upregulated in hepatocytes isolated from inflammation-driven human HCC tumors and matching paracancerous tissues. Tetrachloromethane (CCl4)-induced and diethylnitrosamine (DEN)-induced murine models of inflammatory hepatocarcinogenesis displayed significant hepatocellular TNF and CCR10 upregulation. Exogenous TNF applied to HepG2 and LO2 cell lines as well as wild-type (WT) mice significantly upregulated hepatocellular CCR10 expression, Akt phosphorylation, PCNA expression, and hepatocellular proliferation. Additionally, exogenous TNF significantly upregulated secretion of the natural CCR10 ligand-agonist CCL28 from both cell lines. Transgenic CCR10-knockout (CCR10 KO) in DEN-treated mice significantly increased hepatocellular apoptosis levels and significantly lowered compensatory hepatocellular proliferation but did not affect upstream TNF expression. In addition, DEN-treated CCR10 KO mice showed a significantly lower liver weight/body weight ratio, significantly lower liver tumor incidence, and significantly smaller tumors. Moreover, exogenous CCR10 expression significantly raised xenograft tumor growth in Balb/c nude mice. In vitro, CCR10 transfection or CCL28 treatment in HepG2 and LO2 cell lines significantly increased Akt phosphorylation, PCNA expression, and cell proliferation, while CCR10 silencing or Akt inhibition produced the opposite effects. In vivo, hepatocytes isolated from HCC tumor tissue and matching paracancerous tissue in DEN-treated CCR10 KO mice showed significantly lower Akt phosphorylation and PCNA expression relative to WT hepatocytes. In conclusion, inflammation-induced TNF promotes hepatocellular CCR10 expression and downstream PI3K/Akt-mediated hepatocarcinogenesis. CCR10 appears to function as a linkage between TNF stimulation and downstream PI3K/Akt pathway activation and shows promise as a potential therapeutic target for inflammation-driven HCC.

Dataset Information

Loss of estrogen-related receptor ? promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances.

Publications

Loss of estrogen-related receptor α promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets