title: Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma.
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.
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Xing-Gang
authors.initials: XG
authors.lastname: Mao
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Northern Hospital, General Hospital of PLA Shenyang Military Area Command, Shenyang, Liaoning Province, People's Republic of China.
authors.forename: Dong-Ye
authors.initials: DY
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Changzheng Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Zi-Chao
authors.initials: ZC
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Mi
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Jing-Yang
authors.initials: JY
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Guang-Dong
authors.initials: GD
authors.lastname: Hou
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Si-Yu
authors.initials: SY
authors.lastname: Miao
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Zi-Xuan
authors.initials: ZX
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Jin-Cheng
authors.initials: JC
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Xue
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D000068258:Bevacizumab / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000074322:Antineoplastic Agents, Immunological; C405620:HILPDA protein, human; D009363:Neoplasm Proteins; D000068258:Bevacizumab
keywords: HIG2; VEGF; antiangiogenic therapy; glioblastoma; hypoxia