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

ABSTRACT: 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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC5482624 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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

Zhou Yiqiang Y Jin Guishan G Mi Ruifang R Zhang Junwen J Zhang Jin J Xu Hengzhou H Cheng Sen S Zhang Yunsheng Y Song Wenjie W Liu Fusheng F

Oncotarget 20170501 22

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 ...[more]

PMID: 28415787

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Project description:BACKGROUND Hypertension could induce many serious diseases, including damage to vascular endothelial cells. As a non-coding RNA, long noncoding RNA (lncRNA) has received much attention in scientific research and has a regulating efficacy on many critical life activities in human body. The level of lncRNA AK094457 is thought to be elevated in hypertensive rats. However, there is no research indicating the relationship between the level of lncRNA AK094457 and vascular endothelial injury. MATERIAL AND METHODS In our study, we used lentiviral to knockdown lncRNA AK094457, and the human umbilical vein endothelial cells (HUVECs) were stimulated by the Ang II to imitate the vascular endothelial cell damage caused by hypertension. The Cell Counting Kit-8 assays were used to detect the cells viability. Western blotting was performed to detect the endothelial nitric oxide synthase (eNOS), p-eNOS and endothelin-1 (ET-1). After that the production of the NO was monitored. At last, the reactive oxygen species (ROS) levels and apoptosis rates were detected in this study. RESULTS According to the results, we found that knockdown lncRNA AK094457 could alleviate the decrease of vascular endothelial cell viability induced by angiotensin II (Ang II). The knockdown of lncRNA AK094457 also relieved the downregulation of eNOS and p-eNOS, and the decreasing of NO release. At the same time, the knockdown of lncRNA inhibited the levels of Ang II-induced proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1, and IL-6) and cell adhesion molecules (vascular cell adhesion molecule 1 [VCAM-1], intercellular adhesion molecule 1 [ICAM-1], and monocyte chemoattractant protein-1 [MCP-1]). The levels of ROS and apoptosis rates also decreased after the knockdown of lncRNA AK094457. CONCLUSIONS All these results indicated that lncRNA AK094457 could promote Ang II-induced vascular endothelial cell injury. On the contrary, knockdown of lncRNA AK094457 could alleviate this damage.

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

Publications

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

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