Anti-HIF1A monoclonal antibody, clone 3F22

BackgroundHIF1A (Hypoxia-Inducible-Factor 1A) expression in solid tumors is relevant to establish resistance to therapeutic approaches. The use of compounds direct against hypoxia signaling and HIF1A does not show clinical efficiency because of changeable oxygen concentrations in solid tumor areas. The identification of HIF1A targets expressed in both normoxia and hypoxia and of HIF1A/hypoxia signatures might meliorate the prognostic stratification and therapeutic successes in patients with high-risk solid tumors.MethodsIn this study, we conducted a combined analysis of RNA expression and DNA methylation of neuroblastoma cells silenced or unsilenced for HIF1A expression, grown in normoxia and hypoxia conditions.ResultsThe analysis of pathways highlights HIF-1 (heterodimeric transcription factor 1) activity in normoxia in metabolic process and HIF-1 activity in hypoxia in neuronal differentiation process. HIF1A driven transcriptional response in hypoxia depends on epigenetic control at DNA methylation status of gene regulatory regions. Furthermore, low oxygen levels generate HIF1A-dependent or HIF1A-independent signatures, able to stratify patients according to risk categories.ConclusionsThese findings may help to understand the molecular mechanisms by which low oxygen levels reshape gene signatures and provide new direction for hypoxia targeting in solid tumor.

Hypoxia occurs frequently in human cancers and promotes stabilization and activation of hypoxia inducible factor (HIF). HIF-1 alpha is specific for the hypoxia response, and its degradation mediated by three enzymes EGLN1, EGLN2 and EGLN3. Although EGLNs expression has been found to be related to prognosis of many cancers, few studies examined DNA methylation in EGLNs and its relationship to prognosis of early-stage non-small cell lung cancer (NSCLC). We analyzed EGLNs DNA methylation data from tumor tissue samples of 1,230 early-stage NSCLC patients, as well as gene expression data from The Cancer Genome Atlas. The sliding windows sequential forward feature selection method and weighted random forest were used to screen out the candidate CpG probes in lung adenocarcinomas (LUAD) and lung squamous cell carcinomas patients, respectively, in both discovery and validation phases. Then Cox regression was performed to evaluate the association between DNA methylation and overall survival. Among the 34 CpG probes in EGLNs, DNA methylation at cg25923056(EGLN2) was identified to be significantly associated with LUAD survival (HR = 1.02, 95% CI: 1.01-1.03, P = 9.90 x 10(-5)), and correlated with EGLN2 expression (r = - 0.36, P = 1.52 x 10(-11)). Meanwhile, EGLN2 expression was negatively correlated with HIF1A expression in tumor tissues (r = - 0.30, P = 4.78 x 10(-8)) and significantly (P = 0.037) interacted with HIF1A expression on overall survival. Therefore, DNA methylation of EGLN2- HIF1A is a potential marker for LUAD prognosis and these genes are potential treatment targets for further development of HIF-1 alpha inhibitors in lung cancer therapy.