| First Author | Hong EJ | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 44 | Pages | 17975-80 |
| PubMed ID | 24127579 | Mgi Jnum | J:201958 |
| Mgi Id | MGI:5516365 | Doi | 10.1073/pnas.1315319110 |
| Citation | Hong EJ, et al. (2013) Loss of estrogen-related receptor alpha promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances. Proc Natl Acad Sci U S A 110(44):17975-80 |
| abstractText | Estrogen-related receptor alpha (ERRalpha) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERRalpha has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERRalpha in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERRalpha accelerates the development of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Biochemical and metabolomics studies revealed that loss of ERRalpha 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 ERRalpha-null livers is concomitant with increased nuclear factor kappaB (NF-kappaB)-dependent transcriptional control of cytokine expression in Kupffer cells. In particular, we demonstrate that loss of ERRalpha-dependent regulation of the NF-kappaB inhibitor IkappaBalpha leads to enhanced NF-kappaB activity and cytokine gene activation. Our work thus shows that global loss of ERRalpha activity promotes hepatocellular carcinoma by independent but synergistic mechanisms in hepatocytes and Kupffer cells, implying that pharmacological manipulation of ERRalpha activity may have a significant clinical impact on carcinogen-induced cancers. |
