Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma

// Xing-gang Mao 1, * , Chao Wang 2, * , Dong-ye Liu 3, * , Xiang Zhang 1 , Liang Wang 2 , Ming Yan 4 , Wei Zhang 1 , Jun Zhu 5 , Zi-chao Li 1 , Chen Mi 1 , Jing-yang Tian 1 , Guang-dong Hou 1 , Si-yu Miao 1 , Zi-xuan Song 1 , Jin-cheng Li 1 , Xiao-yan Xue 6 1 Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China 2 Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China 3 Northern Hospital, General Hospital of PLA Shenyang Military Area Command, Shenyang, Liaoning Province, People’s Republic of China 4 Department of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi Province, People’s Republic of China 5 Department of Orthopedics, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China 6 Department 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 Correspondence to: Xiang Zhang, email: xzhang@fmmu.edu.cn Keywords: hypoxia, glioblastoma, antiangiogenic therapy, HIG2, VEGF Received: February 08, 2016 Accepted: May 17, 2016 Published: June 14, 2016 ABSTRACT 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.