BackgroundHypoxia and inflammation have been identified as hallmarks of cancer. A majority of hepatocellular carcinomas are preceded by hepatitis B- or C-related chronic infections suggesting that liver cancer development is promoted by an inflammatory microenvironment. The inflammatory cytokine oncostatin M (OSM) was shown to induce the expression of hypoxia-inducible factor-1 α (HIF-1 α) under normoxic conditions in hepatocytes and hepatoma cells. HIF-1 α is known to orchestrate the expression of numerous genes, many of which code for metabolic enzymes that play key roles in the adaptation of cellular metabolism to low oxygen tension.ResultsHere, we show that OSM-induced upregulation of HIF-1 α reprograms cellular metabolism in three clones of the human hepatocyte cell line PH5CH (PH5CH1, PH5CH7, and PH5CH8) towards a hypoxia-like metabolic phenotype but has no significant effect on cellular metabolism of HepG2 and JHH-4 hepatoma cells. Although we observed only minor changes in glucose uptake and lactate secretion in PH5CH8 upon OSM treatment, we identified more pronounced changes in intracellular fluxes based on stable isotope labeling experiments. In particular, glucose oxidation in the tricarboxylic acid (TCA) cycle is reduced through pyruvate dehydrogenase kinase 1 (PDK1)-mediated inhibition of the pyruvate dehydrogenase complex, thereby reducing the oxidative TCA cycle flux. As a result of the impaired mitochondrial glucose and glutamine oxidation, the reductive isocitrate dehydrogenase flux was increased.ConclusionsWe provide evidence that connects the inflammatory mediator OSM to a hypoxia-like metabolic phenotype. In the human hepatocyte cell line PH5CH, OSM-mediated upregulation of HIF-1 α and PDK1 can induce hypoxia-like metabolic changes, although to a lesser extent than hypoxia itself. Since PDK1 is overexpressed in several cancers, it might provide a causal link between chronic inflammation and malignant cellular transformation.

中文翻译：

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HIF-1 在制瘤素 M 依赖性肝细胞代谢重编程中的作用

背景缺氧和炎症已被确定为癌症的标志。大多数肝细胞癌之前都有乙型或丙型肝炎相关的慢性感染，这表明炎症微环境促进了肝癌的发展。炎性细胞因子制瘤素 M (OSM) 显示在肝细胞和肝癌细胞的正常氧条件下诱导缺氧诱导因子-1 α (HIF-1 α) 的表达。已知 HIF-1 α 协调许多基因的表达，其中许多基因编码在细胞代谢适应低氧张力中起关键作用的代谢酶。 结果在这里，我们表明 OSM 诱导的 HIF-1 α 上调在人肝细胞系 PH5CH 的三个克隆（PH5CH1、PH5CH7、和 PH5CH8) 趋向于缺氧样代谢表型，但对 HepG2 和 JHH-4 肝癌细胞的细胞代谢没有显着影响。尽管我们在 OSM 处理后仅观察到 PH5CH8 中葡萄糖摄取和乳酸分泌的微小变化，但我们发现基于稳定同位素标记实验的细胞内通量发生了更显着的变化。特别是，三羧酸 (TCA) 循环中的葡萄糖氧化通过丙酮酸脱氢酶激酶 1 (PDK1) 介导的丙酮酸脱氢酶复合物的抑制而减少，从而减少氧化性 TCA 循环通量。由于线粒体葡萄糖和谷氨酰胺氧化受损，还原性异柠檬酸脱氢酶通量增加。结论我们提供了将炎症介质 OSM 与缺氧样代谢表型联系起来的证据。在人肝细胞系 PH5CH 中，OSM 介导的 HIF-1 α 和 PDK1 上调可诱导缺氧样代谢变化，但程度低于缺氧本身。由于 PDK1 在几种癌症中过度表达，它可能提供慢性炎症和恶性细胞转化之间的因果关系。