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Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia‐induced activation of HIF‐1α
Author(s) -
Ji Xiangjun,
Wang Handong,
Zhu Jianhong,
Zhu Lin,
Pan Hao,
Li Wei,
Zhou Yuan,
Cong Zixiang,
Yan Feng,
Chen Suihua
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28699
Subject(s) - gene knockdown , angiogenesis , downregulation and upregulation , cancer research , hypoxia inducible factors , vascular endothelial growth factor , hypoxia (environmental) , transcription factor , rna interference , glioma , biology , cell growth , hif1a , in vitro , microbiology and biotechnology , chemistry , cell culture , gene , rna , vegf receptors , biochemistry , genetics , organic chemistry , oxygen
Concerns were increasingly raised that several types of cancers overexpressed the nuclear factor erythroid 2‐related factor 2 (Nrf2), which contributed strikingly to cancer biological capabilities and chemoresistance. However, the role of Nrf2 in the tumor vascular biology had yet to be mechanistically determined. Here, we investigated the involvement of Nrf2 in glioblastoma (GB) angiogenesis in hypoxia. First, we detected the overexpression of Nrf2 and correlated its protein level with microvessel density (MVD) in human GB tissues. Then, we established the stable RNAi‐mediated Nrf2‐knockdown cells and mimicked hypoxic condition in vitro . The knockdown of Nrf2 inhibited cell proliferation in vitro and suppressed tumor growth in mouse xenografts with a concomitant reduction in VEGF expression and MVD. Similar antiangiogenic effects were documented in endothelial tube formation assays. The downregulation of Nrf2 in glioma cells led to much lower accumulation of HIF‐1α protein and limited expression of VEGF and other HIF‐1α target genes in mimicking hypoxia. Mechanistic investigations suggested that HIF‐1α degradation during hypoxia could be attributed to reduced mitochondrial O 2 consumption in Nrf2‐inhibited cells. It can be concluded that Nrf2, with its capacity for affecting the protein level of HIF‐1α expression, has good reasons to be considered as a critical transcription factor for controlling glioma angiogenesis.