Department of Biochemistry and Molecular Biology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Biochemistry and Molecular Biology and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Arch Biochem Biophys. 2014 Feb 1;543:40-7. doi: 10.1016/j.abb.2013.12.010. Epub 2013 Dec 25.
Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes in response to hypoxia. It has been shown that the levels of peroxisome proliferator-activated receptor γ (PPARγ) are influenced by changes in oxygen tension, and PPARγ plays a critical role in metabolism regulation and cancers. In this research, we observed an increased PPARγ mRNA and protein levels in company with increased HIF-1 protein levels in HepG2 cells in hypoxia as compared with in normoxia. Enforced expression of HIF-1α induced PPARγ1 and PPARγ2 expression, while knockdown of HIF-1α by small interference RNA deduced PPARγ1 and PPARγ2 expression in HepG2 cells under hypoxic conditions. By dual-luciferase reporter assay and chromatin immunoprecipitation assay we confirmed a functional hypoxic response element (HRE) localized at 684bp upstream of the transcriptional start site (TSS) of PPARγ1 and a functional HRE localized at 204bp downstream of the TSS of PPARγ2 in HepG2 cells. Additionally we observed an increase and co-presence of PPARγ and HIF-1α, and a highly positive correlation between PPARγ expression and HIF-1α expression (r=0.553, p<0.0001), in the same tumor tissue areas of hepatocellular carcinoma patients. Our data suggested a new mechanism of hepatocellular carcinoma cells response to hypoxia.
缺氧诱导因子-1（HIF-1）可以激活一系列基因的表达，以应对缺氧。已经表明，过氧化物酶体增殖物激活受体γ（PPARγ）的水平受到氧张力变化的影响，PPARγ 在代谢调节和癌症中起着关键作用。在这项研究中，我们观察到与常氧相比，缺氧时 HepG2 细胞中 HIF-1 蛋白水平升高，同时 PPARγ mRNA 和蛋白水平也升高。HIF-1α 的强制表达诱导了 PPARγ1 和 PPARγ2 的表达，而在缺氧条件下用小干扰 RNA 敲低 HIF-1α 则降低了 HepG2 细胞中 PPARγ1 和 PPARγ2 的表达。通过双荧光素酶报告基因检测和染色质免疫沉淀检测，我们在 HepG2 细胞中证实了 PPARγ1 的转录起始位点（TSS）上游 684bp 处和 PPARγ2 的 TSS 下游 204bp 处存在功能缺氧反应元件（HRE）。此外，我们还观察到肝癌患者肿瘤组织区域中 PPARγ 和 HIF-1α 的增加和共存，以及 PPARγ 表达与 HIF-1α 表达之间存在高度正相关（r=0.553，p<0.0001）。我们的数据表明了肝癌细胞对缺氧反应的新机制。
