RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells
RSUME is implicated in HIF-1-induced VEGF-A production in pituitary tumour cells
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DOI：
10.1530/erc-11-0211
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Renner, U.
中科院分区：
文献类型：
--
作者：
Shan, B.;Gerez, J.;Renner, U.
最近克隆的含有小RWD结构域的蛋白RSUME显示出增加缺氧诱导因子-1 α（HIF-1 α）的蛋白水平。后者是HIF-1的氧调节亚基，HIF-1是细胞对缺氧条件的适应过程中最重要的转录因子。它也是血管内皮生长因子-A（VEGF-A）的主要调节因子，VEGF-A在肿瘤新生血管形成的复杂过程中起关键作用。在这项研究中，RSUME在垂体肿瘤中的表达和作用进行了研究。我们发现RSUME mRNA在垂体腺瘤中表达上调，并与HIF-1 α mRNA水平显著相关。低氧（1%O-2）或模拟低氧的氯化钴处理增强RSUME和HIF-1 α的表达，诱导HIF-1 α易位到细胞核，并刺激垂体瘤细胞系和原代人垂体腺瘤细胞培养物中VEGF-A的产生。当RSUME表达被siRNA特异性下调时，CoCl 2诱导的VEGF-A分泌增加强烈减少，这显示是RSUME敲低相关的HIF-1 α合成减少的结果。因此，RSUME通过调节HIF-1 α水平和随后的VEGF-A产生在启动垂体肿瘤新血管形成中起重要作用，因此可能与垂体腺瘤进展密切相关。内分泌相关癌症（2012）19 13-27
The recently cloned small RWD-domain containing protein RSUME was shown to increase protein levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha). The latter is the oxygen-regulated subunit of HIF-1, the most important transcription factor of the cellular adaptive processes to hypoxic conditions. It is also a major regulator of vascular endothelial growth factor-A (VEGF-A), which is critically involved in the complex process of tumour neovascularisation. In this study, the expression and role of RSUME in pituitary tumours was studied. We found that RSUME mRNA was up-regulated in pituitary adenomas and significantly correlated with HIF-1 alpha mRNA levels. Hypoxia (1% O-2) or treatment with hypoxia-mimicking CoCl2 enhanced RSUME and HIF-1 alpha expression, induced translocation of HIF-1 alpha to the nuclei and stimulated VEGF-A production both in pituitary tumour cell lines and primary human pituitary adenoma cell cultures. When RSUME expression was specifically down-regulated by siRNA, the CoCl2-induced increase VEGF-A secretion was strongly reduced which was shown to be a consequence of the RSUME knockdown-associated reduction of HIF-1 alpha synthesis. Thus, RSUME plays an important role in initiating pituitary tumour neovascularisation through regulating HIF-1 alpha levels and subsequent VEGF-A production and may therefore be critically involved in pituitary adenoma progression. Endocrine-Related Cancer (2012) 19 13-27