GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth.
GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth.
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GPR133 (ADGRD1) 是一种粘附 G 蛋白偶联受体，是胶质母细胞瘤生长所必需的。
DOI：
10.1038/oncsis.2016.63
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发表时间：
2016-10-24
期刊：
影响因子：
6.2
通讯作者：
Placantonakis, D. G.
中科院分区：
文献类型：
--
作者：
Bayin, N. S.;Frenster, J. D.;Kane, J. R.;Rubenstein, J.;Modrek, A. S.;Baitalmal, R.;Dolgalev, I.;Rudzenski, K.;Scarabottolo, L.;Crespi, D.;Redaelli, L.;Snuderl, M.;Golfinos, J. G.;Doyle, W.;Pacione, D.;Parker, E. C.;Chi, A. S.;Heguy, A.;MacNeil, D. J.;Shohdy, N.;Zagzag, D.;Placantonakis, D. G.
胶质母细胞瘤（GBM）是一种致命的原发性脑恶性肿瘤，具有广泛的瘤内缺氧。GBM的低分化区域含有干细胞样细胞，并且与肿瘤生长和血管生成相关。在低氧条件下调节肿瘤生长的分子机制还不完全清楚。在这里，我们使用原发性人类肿瘤生物标本和培养物来鉴定GPR133（ADGRD1），G蛋白偶联受体粘附家族的孤儿成员，作为GBM中缺氧和肿瘤生长反应的关键调节因子。GPR133选择性地表达于CD133+ GBM干细胞（GSC）中以及人生物样本中PPN的缺氧区域内。GPR133 mRNA在低氧诱导因子1α（Hif1α）依赖性下转录上调。用短发夹RNA对GPR133的遗传抑制降低了体外CD133+ GSC的患病率、肿瘤细胞增殖和肿瘤球形成。毛喉素拯救GPR133敲低表型，表明GPR133信号传导由cAMP介导。在小鼠脑中植入具有短发夹RNA介导的GPR133敲低的GBM细胞显著减少肿瘤异种移植物形成并增加宿主存活。TCGA数据的分析显示GPR133表达水平与患者存活率呈负相关。这些发现表明GPR133是GBM中缺氧反应的重要介质，并且具有显著的促肿瘤发生功能。我们认为GPR133代表了GBM和可能的其他恶性肿瘤的一个新的分子靶点，其中缺氧是发病机制的基础。
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
DOI：
10.4161/cc.8.20.9701
发表时间：
2009-10-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
通讯作者：
Rich JN
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
3.7
作者：
Bayin, N. Sumru;Modrek, Aram S.;Placantonakis, Dimitris G.
通讯作者：
Placantonakis, Dimitris G.
影响因子：
3.9
作者：
Christensen, Karina;Schroder, Henrik Daa;Kristensen, Bjarne Winther
通讯作者：
Kristensen, Bjarne Winther