Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway.
Hypoxia inducible factor 2 alpha inhibits hepatocellular carcinoma growth through the transcription factor dimerization partner 3/ E2F transcription factor 1-dependent apoptotic pathway.
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缺氧诱导因子 2 α 通过转录因子二聚化伴侣 3/E2F 转录因子 1 依赖性细胞凋亡途径抑制肝细胞癌生长。
DOI：
10.1002/hep.26188
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发表时间：
2013-03
期刊：
影响因子：
13.5
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Sun, Hai-Xiang;Xu, Yang;Yang, Xin-Rong;Wang, Wei-Min;Bai, Haibo;Shi, Ruo-Yu;Nayar, Suresh K.;Devbhandari, Ranjan P.;He, Yi-zhou;Zhu, Qin-Feng;Sun, Yun-Fan;Hu, Bo;Khan, Mehtab;Anders, Robert A.;Fan, Jia
低氧诱导因子（HIF）在许多肿瘤中被激活，并根据肿瘤细胞生物学和背景显示启动子或抑制子活性。然而，HIF-2α在肝细胞癌（HCC）中的作用尚不清楚。本研究采用qRT-PCR、Western blot和免疫荧光法检测246例HCC患者及其癌旁组织中HIF-2α的表达，并探讨其临床意义。在细胞培养中，分别用表达质粒和短发夹RNA重组质粒过量表达或敲低HIF-2α水平。通过免疫印迹、染色质免疫沉淀结合微阵列、免疫共沉淀和组织化学染色对细胞进行分析。在裸鼠中分析体内肿瘤生长。我们发现，肝癌组织中HIF-2α的平均表达相对较低，并且水平降低与总生存率降低相关（p=0.006）。肝癌细胞中HIF-2α的高表达可诱导细胞凋亡和促凋亡蛋白的高水平表达，并抑制细胞和肿瘤的生长。此外，HIF-2α抑制新靶基因转录因子二聚化伴侣3（TFDP 3）的表达。发现TFDP 3蛋白与E2 F转录因子1（E2 F1）结合并通过p53依赖性和非依赖性途径抑制其转录活性。重新引入TFDP 3表达逆转了HIF-2α诱导的细胞凋亡。从细胞系、致瘤性研究和原发性HCC样本中收集的数据表明，HIF-2α在肿瘤中具有负面作用，这是由TFDP 3/E2 F1通路介导的。我们的研究提供了支持HIF-2α可能的肿瘤抑制作用的证据，并揭示了一种将HIF-2α与基本生物调节因子E2 F1联系起来的机制。
Hypoxia inducible factors (HIFs) are activated in many tumors and show either promoter or suppressor activity depending on the tumor cell biology and background. However, the role of HIF member HIF-2α remains unclear in hepatocellular carcinoma (HCC). Here, HIF-2α expression was measured in HCC and paired peritumoral tissues by qRT-PCR, western blot analysis, and immunofluorescence assays, and the clinical significance was explored in 246 HCC patients. In cell culture, HIF-2α levels were over-expressed or knocked-down by use of expression or short hairpin RNA recombinant plasmid respectively. Cells were analyzed by immunoblot, chromatin immunoprecipitation coupled with microarray, co-immunoprecipitation, and histochemical staining. In vivo tumor growth was analyzed in nude mice. We found that the average expression of HIF-2α was relatively low in HCC tissues, and the decreased level was associated with lower overall survival (p=0.006). High HIF-2α expression in HCC cells induced higher levels of apoptosis and expression of pro-apoptotic proteins, and it inhibited cell and tumor growth. Furthermore, HIF-2α inhibited expression of the novel target gene transcription factor dimerization partner 3 (TFDP3). TFDP3 protein was found to bind with E2F transcription factor 1 (E2F1) and inhibit its transcriptional activity through both p53-dependent and -independent pathways. Re-introduction of TFDP3 expression reversed HIF-2α-induced apoptosis. Data gathered from cell lines, tumorigenicity studies, and primary HCC samples demonstrate a negative role of HIF-2α in tumors, which is mediated by the TFDP3/E2F1 pathway. Our study provides evidence supporting a possible tumor suppressor role for HIF-2α and has uncovered a mechanism that links HIF-2α to a fundamental biological regulator, E2F1.
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基于肿瘤微环境的癌细胞杀伤的背景综合致死率。
影响因子：
11.2
作者：
Chan N;Pires IM;Bencokova Z;Coackley C;Luoto KR;Bhogal N;Lakshman M;Gottipati P;Oliver FJ;Helleday T;Hammond EM;Bristow RG
通讯作者：
Bristow RG
影响因子：
50.3
作者：
Blouw, B;Song, HQ;Bergers, G
通讯作者：
Bergers, G
缺氧诱导因子 1 α 与炎症、血管生成和 MYC 相关，是 HCC 患者术后的关键预后因素。
影响因子：
3.8
作者：
Dai CX;Gao Q;Qiu SJ;Ju MJ;Cai MY;Xu YF;Zhou J;Zhang BH;Fan J
通讯作者：
Fan J
影响因子：
45.3
作者：
Gao, Qiang;Qiu, Shuang-Jian;Tang, Zhao-You
通讯作者：
Tang, Zhao-You
DOI：
10.1073/pnas.95.9.4997
发表时间：
1998-04-28
影响因子：
11.1
作者：
Jürgensmeier, JM;Xie, ZH;Reed, JC
通讯作者：
Reed, JC