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.

中文翻译：

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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。

肝细胞癌（HCC）的发展取决于其局部微环境，而新血管形成的诱导是肿瘤进展的决定性步骤，因为实体瘤的生长受到营养和氧气供应的限制。缺氧是诱导缺氧诱导因子-1α（HIF-1α）编码基因HIF1A和HIF-1α蛋白积累以促进血管生成的转录的关键因素。但是，尚不清楚HCC中HIF1A表达的转录调控的基础。在这里，我们显示Bclaf1水平与HCC组织中的HIF-1α水平高度相关，而敲除Hcla细胞系中的Bclaf1则显着降低了缺氧诱导的HIF1A表达。此外，我们发现Bclaf1通过其bZIP结构域促进HIF1A转录，继而导致HIF-1α下游靶标VEGFA，TGFB和EPO的转录增加，进而促进HCC相关的血管生成，从而促进HCC细胞的存活和繁荣。此外，我们证明在异种移植肿瘤中shRNA介导的Bclaf1敲低后，HIF-1α水平和微血管密度降低。最后，我们发现缺氧状态下Bclaf1水平以HIF-1α依赖性方式增加。因此，我们的研究确定Bclaf1为低氧微环境中HIF-1α的新型正调节剂，为促进Bcalf1作为抗HCC策略的潜在治疗靶标提供了新的诱因。我们证明了在异种移植肿瘤中shRNA介导的Bclaf1敲低后，HIF-1α水平和微血管密度降低。最后，我们发现缺氧状态下Bclaf1水平以HIF-1α依赖性方式增加。因此，我们的研究确定Bclaf1为低氧微环境中HIF-1α的新型正调节剂，为促进Bcalf1作为抗HCC策略的潜在治疗靶标提供了新的诱因。我们证明了在异种移植肿瘤中shRNA介导的Bclaf1敲低后，HIF-1α水平和微血管密度降低。最后，我们发现缺氧状态下Bclaf1水平以HIF-1α依赖性方式增加。因此，我们的研究确定Bclaf1为低氧微环境中HIF-1α的新型正调节剂，为促进Bcalf1作为抗HCC策略的潜在治疗靶标提供了新的诱因。