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功能获得性GLI1转录因子TGLI1增强VEGF-C和TEM7的表达以促进胶质母细胞瘤血管生成。

The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.

作者信息

Carpenter Richard L, Paw Ivy, Zhu Hu, Sirkisoon Sherona, Xing Fei, Watabe Kounosuke, Debinski Waldemar, Lo Hui-Wen

机构信息

Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.

出版信息

Oncotarget. 2015 Sep 8;6(26):22653-65. doi: 10.18632/oncotarget.4248.

DOI:10.18632/oncotarget.4248
PMID:26093087
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4673189/
Abstract

We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we compared TGLI1- with GLI1-expressing GBM xenografts for the expression profile of 84 angiogenesis-associated genes. The results showed that expression of six genes were upregulated and five were down-regulated in TGLI1-carrying tumors compared to those with GLI1. Vascular endothelial growth factor-C (VEGF-C) and tumor endothelial marker 7 (TEM7) were selected for further investigations because of their significant correlations with high vascularity in 135 patient GBMs. TGLI1 bound to both VEGF-C and TEM7 gene promoters. Conditioned medium from TGLI1-expressing GBM cells strongly induced tubule formation of brain microvascular endothelial cells, and the induction was prevented by VEGF-C/TEM7 knockdown. Immunohistochemical analysis of 122 gliomas showed that TGLI1 expression was positively correlated with VEGF-C, TEM7 and microvessel density. Analysis of NCBI Gene Expression Omnibus datasets with 161 malignant gliomas showed an inverse relationship between tumoral VEGF-C, TEM7 or microvessel density and patient survival. Together, our findings support an important role that TGLI1 plays in GBM angiogenesis and identify VEGF-C and TEM7 as novel TGLI1 target genes of importance to GBM vascularity.

摘要

我们最近发现，截短的胶质瘤相关癌基因同源物1（TGLI1）在胶质母细胞瘤（GBM）中高表达，并与GBM血管生成增加有关。TGLI1介导血管生成的潜在机制尚不清楚。在本研究中，我们比较了表达TGLI1与表达GLI1的GBM异种移植瘤中84个血管生成相关基因的表达谱。结果显示，与携带GLI1的肿瘤相比，携带TGLI1的肿瘤中有6个基因的表达上调，5个基因的表达下调。血管内皮生长因子C（VEGF-C）和肿瘤内皮标志物7（TEM7）因其与135例GBM患者肿瘤高血管生成显著相关而被选择进行进一步研究。TGLI1与VEGF-C和TEM7基因启动子均结合。表达TGLI1的GBM细胞的条件培养基强烈诱导脑微血管内皮细胞形成小管，而VEGF-C/TEM7基因敲低可阻止这种诱导。对122例胶质瘤的免疫组织化学分析表明，TGLI1表达与VEGF-C、TEM7和微血管密度呈正相关。对161例恶性胶质瘤的NCBI基因表达综合数据集分析显示，肿瘤VEGF-C、TEM7或微血管密度与患者生存率呈负相关。总之，我们的研究结果支持TGLI1在GBM血管生成中发挥重要作用，并确定VEGF-C和TEM7是对GBM血管生成至关重要的新型TGLI1靶基因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/a30a542ad176/oncotarget-06-22653-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/c502141a39d3/oncotarget-06-22653-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/80cbd9c83f8f/oncotarget-06-22653-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/df20d85aadbc/oncotarget-06-22653-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/a30a542ad176/oncotarget-06-22653-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/c502141a39d3/oncotarget-06-22653-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/0ec3bd3c6668/oncotarget-06-22653-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/689e088c9821/oncotarget-06-22653-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/6855e76e8da0/oncotarget-06-22653-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/80cbd9c83f8f/oncotarget-06-22653-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/df20d85aadbc/oncotarget-06-22653-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bd5/4673189/a30a542ad176/oncotarget-06-22653-g007.jpg

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