Bclaf1 promotes angiogenesis by regulating HIF-1α transcription in hepatocellular carcinoma.
Bclaf1 promotes angiogenesis by regulating HIF-1α transcription in hepatocellular carcinoma.
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Bclaf1 通过调节肝细胞癌中的 HIF-1α 转录来促进血管生成。
DOI：
10.1038/s41388-018-0552-1
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Wen Y;Zhou X;Lu M;He M;Tian Y;Liu L;Wang M;Tan W;Deng Y;Yang X;Mayer MP;Zou F;Chen X
肝细胞癌（HCC）的发展取决于其局部微环境，并且由于实体肿瘤的生长受到营养和氧气供应的限制，因此诱导新血管形成是肿瘤进展中的决定性步骤。缺氧是诱导缺氧诱导因子-1 α（HIF-1α）编码基因HIF 1A转录和蛋白积累促进血管生成的关键因素。然而，HCC中HIF 1A表达的转录调控基础仍不清楚。在这里，我们发现肝癌组织中Bclaf 1水平与HIF-1α水平高度相关，并且肝癌细胞系中Bclaf 1的敲低显著降低了缺氧诱导的HIF-1A表达。此外，我们发现Bclaf 1通过其bZIP结构域促进HIF 1A转录，随后导致HIF-1α下游靶点VEGFA、TGFB和EPO的转录增加，从而促进HCC相关的血管生成，从而促进HCC细胞的存活和繁荣。此外，我们证明了在异种移植肿瘤中，在shRNA介导的Bclaf 1敲低后，HIF-1α水平和微血管密度降低。最后，我们发现Bclaf 1水平在缺氧中以HIF-1α依赖性方式增加。因此，我们的研究将Bclaf 1鉴定为缺氧微环境中HIF-1α的新型正调节因子，为促进Bcalf 1作为抗HCC策略的潜在治疗靶点提供了新的激励。
The development of hepatocellular carcinomas (HCC) depends on their local microenvironment and the induction of neovascularization is a decisive step in tumor progression, since the growth of solid tumors is limited by nutrient and oxygen supply. Hypoxia is the critical factor that induces transcription of the hypoxia inducible factor-1α (HIF-1α) encoding gene HIF1A and HIF-1α protein accumulation to promote angiogenesis. However, the basis for the transcriptional regulation of HIF1A expression in HCC is still unclear. Here, we show that Bclaf1 levels are highly correlated with HIF-1α levels in HCC tissues, and that knockdown of Bclaf1 in HCC cell lines significantly reduces hypoxia-induced HIF1A expression. Furthermore, we found that Bclaf1 promotes HIF1A transcription via its bZIP domain, leading subsequently to increased transcription of the HIF-1α downstream targets VEGFA, TGFB, and EPO that in turn promote HCC-associated angiogenesis and thus survival and thriving of HCC cells. Moreover, we demonstrate that HIF-1α levels and microvessel density decrease after the shRNA-mediated Bclaf1 knockdown in xenograft tumors. Finally, we found that Bclaf1 levels increase in hypoxia in a HIF-1α dependent manner. Therefore, our study identifies Bclaf1 as a novel positive regulator of HIF-1α in the hypoxic microenvironment, providing new incentives for promoting Bcalf1 as a potential therapeutic target for an anti-HCC strategy.
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影响因子：
29.4
作者：
El-Serag HB
通讯作者：
El-Serag HB
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
11.2
作者：
Doe MR;Ascano JM;Kaur M;Cole MD
通讯作者：
Cole MD
影响因子：
--
作者：
Sarras H;Alizadeh Azami S;McPherson JP
通讯作者：
McPherson JP
DOI：
10.1016/j.bbrc.2015.07.037
发表时间：
2015-09-04
影响因子：
3.1
作者：
Ju, Uk-Il;Park, Jong-Wan;Chun, Yang-Sook
通讯作者：
Chun, Yang-Sook