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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. HIF1? bound to the HIG2 promoter and increased its expression in GBM cells, and HIG2 upregulated HIF1? 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.

SUBMITTER: Mao XG

PROVIDER: S-EPMC5216980 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma.

Mao Xing-Gang XG Wang Chao C Liu Dong-Ye DY Zhang Xiang X Wang Liang L Yan Ming M Zhang Wei W Zhu Jun J Li Zi-Chao ZC Mi Chen C Tian Jing-Yang JY Hou Guang-Dong GD Miao Si-Yu SY Song Zi-Xuan ZX Li Jin-Cheng JC Xue Xiao-Yan XY

Oncotarget 20160701 30

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 ...[more]

PMID: 27329597

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Project description:BACKGROUND: Glioblastoma (GBM) remains an incurable malignancy with rapid progression and poor survival. GBM exhibits a hypoxic nature, and treatment with bevacizumab (BEV) may increase intratumoral hypoxia. TH-302 is an investigational prodrug that selectively releases the DNA cross-linker (Br-IPM) under hypoxic conditions. A phase I/II trial (NCT01403610) is evaluating the safety and efficacy of combined TH-302 and BEV treatment in patients with BEV-refractory GBM and investigating pharmacodynamics biomarkers. METHODS: Patients were randomized to TH-302 single dose (575 mg/m2) or placebo, administered one day before surgery, followed by TH-302 (240-670 mg/m2) + BEV treatment until disease progression. Before surgery, pimonidazole (Pimo) was administered to label hypoxia and the excised tumor tissue was processed for immunohistochemistry. Endogenous plasma metabolites and plasma carbonic anhydrase IX (CA-IX) were also assessed. RESULTS: Immunohistochemistry was conducted on 11 resected tumors. A strong correlation and co-localization was observed between Pimo (exogenous hypoxia marker) and CA-IX (endogenous hypoxia marker) expression (r = 0.9, p < 0.001). Plasma CA-IX levels correlated well with tissue CA-IX expression. The hypoxic fraction tended to be higher in patients with a stable disease or partial tumor responses. Patients treated with TH-302 prior to surgery tended to have higher levels of ?H2AX positive cells, indicating increased DNA damage, and lower Ki67 (a proliferation marker) compared with patients who received placebo. Patients treated with a single dose of TH-302 prior to surgery with higher levels of ?H2AX-positive cells tended to have better outcome. Metabolomic profiles in plasma and in tumor tissue differed with degree of hypoxia. CONCLUSION: The results suggest that CA-IX as a hypoxia marker might be a predictive biomarker for TH-302 and ?H2AX a response biomarker for TH-302. Correlative studies show metabolomic profile varies with tumor hypoxia degree, indicating plasma metabolites for further study as potential prognostic or treatment response markers.

Dataset Information

Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma.

Publications

Hypoxia upregulates HIG2 expression and contributes to bevacizumab resistance in glioblastoma.

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