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Gene expression profiling data following HIF-1α or HIF-2α knockdown in SW1353 cells

ABSTRACT: Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. We aimed to uncover the transcriptional program directing such tumor progression in chondrosarcomas. Here, we conducted weighted correlation network analysis (WGCNA) to extract a characteristic gene module underlying chondrosarcoma malignancy. We identified hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) as an upstream regulator that governs the malignancy gene module. HIF-2α was upregulated in high grade chondrosarcoma biopsies and HIF-2α gene amplification was associated with the poor prognosis of patients with chondrosarcoma. Using tumor xenograft mouse models, we demonstrated that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Pharmacological inhibition of HIF-2α in conjunction with the chemotherapy agents synergistically enhanced chondrosarcoma cell apoptosis and abolished malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of novel molecular-targeted therapeutics for chondrosarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156565 | GEO | 2020/08/21

REPOSITORIES: GEO

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Project description:To investigate the detailed molecular mechanisms for the regulatory role of HIF-2α in experimental colitis, microarray gene expression analysis was performed on colon RNA isolated from 6- to 8-week-old Hif-2αF/F, Hif-2αlΔIE mice treated with 3%DSS for 3 days. Background & Aims: Hypoxic inflammation is characterized by decreased oxygen tension in inflammatory foci, and is a notable feature in inflammatory bowel disease (IBD). Hypoxic response is mediated by transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α, both of which are highly induced in IBD. HIF-1α is a protective factor that limits intestinal barrier dysfunction during inflammation. However, the role of HIF-2α has not been assessed in hypoxic inflammation and IBD. Methods: A hypoxia reporter mouse model was used to test the presence of hypoxia and HIF-2α in dextran sulfate sodium (DSS) and Citrobacter rodentium (C.rod)-induced colitis. The role of HIF-2α in these mouse models of colitis was further assessed in mice with an intestinal epithelium-specific gain- and loss-of-function of HIF-2α. Results: Induction of hypoxia and HIF-2α was confirmed in both murine experimental colitis models and human IBD samples. Disruption of HIF-2α attenuated colonic inflammation whereas stabilization of HIF-2α potentiated inflammation in mouse models of colitis. Interestingly, intestine specific overexpression of HIF-2α but not HIF-1α leads to spontaneous colitis and premature death in mice. Further mechanistic analysis showed that HIF-2α is a driver for pro-inflammatory response and is critical regulator of intestinal epithelial-derived tumor necrosis factor (TNF)-α. Blocking TNF-α completely ameliorated HIF-2α potentiated intestinal inflammation. Conclusions: These data demonstrate that HIF-2α is a critical transcription factor essential in intestinal epithelium elicited inflammatory response. Global gene expression profiling in colon RNAs isolated from 7-week-old Hif-2αF/F (n=6, Shah 007) and Hif-2αΔIE (n=5, Shah 008).

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Gene expression profiling data following HIF-1α or HIF-2α knockdown in SW1353 cells

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