Knockdown of P4HA1 inhibits neovascularization via targeting glioma stem cell-endothelial cell transdifferentiation and disrupting vascular basement membrane

被引：36

作者：

Zhou, Yiqiang ^{[1
,2
]}

Jin, Guishan ^{[1
,3
]}

Mi, Ruifang ^{[1
,3
]}

Zhang, Junwen ^{[1
,3
]}

Zhang, Jin ^{[1
,2
]}

Xu, Hengzhou ^{[1
,2
]}

Cheng, Sen ^{[1
,2
]}

Zhang, Yunsheng ^{[1
,2
]}

Song, Wenjie ^{[1
,2
]}

Liu, Fusheng ^{[1
,2
,3
]}

机构：

[1] Beijing Neurosurg Inst, Brain Tumor Res Ctr, Beijing 100050, Peoples R China

[2] Capital Med Univ, Dept Neurosurg, Beijing Tiantan Hosp, Beijing 100050, Peoples R China

[3] Beijing Lab Biomed Mat, Beijing 100050, Peoples R China

来源：

ONCOTARGET | 2017年 / 8卷 / 22期

关键词：

glioma stem cells; neovascularization; transdifferentiation; P4HA1; GROWTH-FACTOR; IN-VIVO; TUMOR ANGIOGENESIS; CHANNEL FORMATION; BRAIN-TUMORS; COLLAGEN; EXPRESSION; INVASION; PROTEIN; DIFFERENTIATION;

D O I：

10.18632/oncotarget.16270

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Emerging evidence has demonstrated transdifferentiation process of glioma stem cells (GSCs) into endothelial cells (ECs) in glioma neovascularization. Herein, we focused on screening for genes that were differentially expressed in the transdifferentiation process using microarray analysis. Bioinformatics analysis revealed differential expression of the prolyl 4-hydroxylase subunit alpha-1 (P4HA1) gene. We determined that P4HA1 expression was correlated with histological grade, the level of Ki67 and microvessel density (MVD) in human glioma specimens. Knockdown of P4HA1 inhibited the proliferation, migration and tube formation of GSCs in vitro. In vivo studies revealed that the downregulation of P4HA1 inhibited intracranial tumor growth, prolonged the overall survival time of xenograft mice and suppressed the neovascularization in brain tumors. Moreover, P4HA1 regulates the expression of vascular endothelial growth factor A (VEGF-A), especially an anti-angiogenic isoform-VEGF165b. Additionally, knockdown of P4HA1 inhibited the synthesis of collagen IV, and hence disrupted the structures of vascular basement membranes (BMs) in gliomas. Our study indicates that P4HA1 plays a pivotal role in the process of GSC-EC transdifferentiation and the structural formation of vascular BMs.

引用

页码：35877 / 35889

页数：13