Loss of estrogen-related receptor a promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances
Loss of estrogen-related receptor a promotes hepatocarcinogenesis development via metabolic and inflammatory disturbances
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DOI：
10.1073/pnas.1315319110
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发表时间：
2013-10-29
影响因子：
11.1
通讯作者：
Giguere, Vincent
中科院分区：
文献类型：
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作者：
Hong, Eui-Ju;Levasseur, Marie-Pier;Giguere, Vincent
雌激素相关受体a（ERRa）是正常细胞和癌细胞中能量驱动的细胞过程所必需的线粒体功能和代谢的关键调节剂。ERRa还被证明通过促炎细胞因子介导骨源性巨噬细胞活化。然而，ERRa在炎症作为肿瘤促进剂的癌症中的作用还有待研究。在这里，我们表明，全球损失的ERRa加速二乙基亚硝胺（DEN）诱导的肝细胞癌的发展。生物化学和代谢组学研究表明，ERRa的损失促进肝细胞坏死超过细胞凋亡，以响应DEN由于能量生产不足。我们进一步表明，在DEN损伤的ERRa缺失肝脏中观察到的肝细胞死亡增加和相关的代偿性增殖伴随着枯否细胞中细胞因子表达的核因子κ B（NF-κ B）依赖性转录控制增加。特别是，我们证明了NF-kappa B抑制剂I.Ba的ERR α依赖性调节的丧失导致增强的NF-kappa B活性和细胞因子基因活化。因此，我们的工作表明，ERRa活性的全球损失促进肝细胞癌的肝细胞和枯否细胞中的独立但协同的机制，这意味着ERRa活性的药理学操作可能有显着的临床影响致癌物诱导的癌症。
Estrogen-related receptor a (ERRa) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERRa has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERRa in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERRa accelerates the development of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Biochemical and metabolomics studies revealed that loss of ERRa 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 ERRa-null livers is concomitant with increased nuclear factor kappa B (NF-kappa B)-dependent transcriptional control of cytokine expression in Kupffer cells. In particular, we demonstrate that loss of ERR alpha-dependent regulation of the NF-kappa B inhibitor I.Ba leads to enhanced NF-kappa B activity and cytokine gene activation. Our work thus shows that global loss of ERRa activity promotes hepatocellular carcinoma by independent but synergistic mechanisms in hepatocytes and Kupffer cells, implying that pharmacological manipulation of ERRa activity may have a significant clinical impact on carcinogen-induced cancers.