Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma
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Xing-gang Mao1,*, Chao Wang2,*, Dong-ye Liu3,*, Xiang Zhang1, Liang Wang2, Ming Yan4, Wei Zhang1, Jun Zhu5, Zi-chao Li1, Chen Mi1, Jing-yang Tian1, Guang-dong Hou1, Si-yu Miao1, Zi-xuan Song1, Jin-cheng Li1, Xiao-yan Xue6
1Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China
2Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China
3Northern Hospital, General Hospital of PLA Shenyang Military Area Command, Shenyang, Liaoning Province, People’s Republic of China
4Department of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China
5Department of Orthopedics, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China
6Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China
*These authors have contributed equally to this work
Xiang Zhang, email: [email protected]
Keywords: hypoxia, glioblastoma, antiangiogenic therapy, HIG2, VEGF
Received: February 08, 2016 Accepted: May 17, 2016 Published: June 14, 2016
Hypoxia contributes to the maintenance of stem-like cells in glioblastoma (GBM), and activates vascular mimicry and tumor resistance to anti-angiogenesis treatments. The present study examined the expression patterns and biological significance of hypoxia-inducible protein 2 (HIG2, also known as HILPDA) in GBM. HIG2 was highly expressed in gliomas and was correlated with tumor grade, and high HIG2 expression independently predicted poor GBM patient prognosis. HIG2 was upregulated during hypoxia and by hypoxia mimics, and HIG2 knockdown in GBM cells inhibited cell proliferation and invasion. HIF1α bound to the HIG2 promoter and increased its expression in GBM cells, and HIG2 upregulated HIF1α expression. Reconstruction of a HIG2-related molecular network using bioinformatics methods revealed that HIG2 is closely correlated with angiogenesis genes, such as VEGFA, in GBM. HIG2 levels positively correlated with VEGFA in GBM samples. In addition, treatment of transplanted xenograft nude mice with bevacizumab (anti-angiogenesis therapy) resulted in HIG2 upregulation at late stages. We conclude that HIG2 is overexpressed in GBM and upregulated by hypoxia, and is a potential novel therapeutic target. HIG2 overexpression is an independent prognostic indicator and may promote tumor resistance to anti-angiogenesis treatments.
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