OSLN Reprogramming cells: empty vector vs. HIF2α over-expression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE54898 | GEO | 2014/05/01
SECONDARY ACCESSION(S): PRJNA238230
REPOSITORIES: GEO
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Project description:Transcriptional profiling of Oct4, Sox2, Lin28 and Nanog (OSLN) reprogramming cell of empty vector compared to HIF2M-NM-1 over-expression at the early stage (day 12) and the late stage(day 30) using fibroblasts MRC5 and IMR90 Eight-condition experiment, empty vector vs. HIF2M-NM-1 over-expression cells, at early stage vs. late stage, and fibroblasts MRC5 vs. IMR90
2014-05-01 | E-GEOD-54898 | biostudies-arrayexpress
Project description:Background: in clear cell renal cell carcinoma (ccRCC), 80% of cases have biallelic inactivation of VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods: we generated the 786-0 HIF2α knockout (KO) cell line and assessed the HIF2α antagonist PT2385 in several steps of tumour development. RNA sequencing was performed to identify genes differentially expressed between them and a drug screening was used to identify drugs with differential effects on HIF2α-expressing and KO cells. Results: HIF2α KO promoted cell migration, reduced proliferation and clonogenicity, as well as metastasis, whereas PT2385 treatment only inhibited tumour cell invasion. There was a large set of co-ordinately regulated genes, but HIF2α KO cells also had up-regulation of genes related to EMT and downregulation of genes involving cell migration and extracellular matrix. The HIF2α KO increased sensitivity to statins, while PT2385 had no effect. Conclusions: this study shows new pathways that could be targeted combined with PT2385 to enhance its therapeutic effects and delay resistance.
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Project description:Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension(PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells(SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here we report that hypoxia-inducible factor 2α(HIF2α) expression is increased in human PAH patient lung tissues and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension(PH) models, we show HIF2α as a major molecular regulator for pericytes’ transformation into SMC-like cells. HIF2α overexpression in pericyte-selective mice exacerbate PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the potential role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
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Project description:Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To establish whether PPGL phenotypic differences reflect a MAX-mediated mechanism and opposing influences of HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α has opposing actions to HIF2α. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes. PC12 cell lines were cultured, one transfected with an emply vector (PC12wt) and the other transfected with an expression plasmid coding the MAX gene. In total four samples were hybridized, each experimental condition had two biological replicates obtained at two different cell passages (8 and 13).
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Project description:Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2α) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.
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Project description:HIF1α promotes glioblastoma cell proliferation and tumorigenesis under hypoxia conditions, leading to poor prognosis; however, none of the targeted therapies of HIF1α for glioblastoma is success nowadays. Therefore, we focused to look for the reason and wondered whether HIF2α contributed GBM growth. We did gene-chip and found that HIF2α contributed to the malignant progression of glioblastoma while blocking of HIF1α. Furthermore, our results revealed knock-out of HIF1α and HIF2α simultaneously improved the chemo-sensitization significantly. Moreover, miR-210-3p induced HIF1α expression but inhibited HIF2α, which meant the existence of regulation of cycle between HIF1α/HIF2α and miR-210-3p. Traditional studies have proved EGF as an upstream gene regulator of HIF1α in hypoxia conditions through EGFR-PI3K/AKT-mTOR signaling pathway. However, in this study, besides the signaling pathways mentioned above, we found the upstream regulators HIF1α and HIF2α also promoted EGF with the binding regions AGGCGTGG and GGGCGTGG. Briefly, in hypoxia microenvironment HIF1α/HIF2α-miR210-3p network promotes malignant progression of glioblastoma through EGFR-PI3K/AKT-mTOR signaling pathway with a positive feedback.
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Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNAdemethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.
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Project description:Neuroblastoma is a pediatric cancer characterized by variable outcomes ranging from spontaneous regression to life-threatening progression. High-risk neuroblastoma patients receive myeloablative chemotherapy with hematopoietic stem-cell transplant followed by adjuvant retinoid differentiation treatment. However, the overall survival remains low; hence, there is an urgent need for alternative therapeutic approaches. One feature of high-risk neuroblastoma is the high level of DNA methylation of putative tumor suppressors. Combining the reversibility of DNA methylation with the differentiation-promoting activity of retinoic acid (RA) could provide an alternative strategy to treat high-risk neuroblastoma. Here we show that treatment with the DNA demethylating drug 5-Aza-deoxycytidine (AZA) restores high-risk neuroblastoma sensitivity to RA. Combined systemic distribution of AZA and RA impedes tumor growth and prolongs survival. Genomewide analysis of treated tumors reveals that this combined treatment rapidly induces a HIF2α-associated hypoxia-like transcriptional response followed by an increase in neuronal gene expression and a decrease in cell-cycle gene expression. A small-molecule inhibitor of HIF2α activity diminishes the tumor response to AZA+RA treatment, indicating that the increase in HIF2α levels is a key component in tumor response to AZA+RA. The link between increased HIF2α levels and inhibited tumor growth is reflected in large neuroblastoma patient datasets. Therein, high levels of HIF2α, but not HIF1α, significantly correlate with expression of neuronal differentiation genes and better prognosis but negatively correlate with key features of high-risk tumors, such as MYCN amplification. Thus, contrary to previous studies, our findings indicate an unanticipated tumor-suppressive role for HIF2α in neuroblastoma.
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Project description:Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To establish whether PPGL phenotypic differences reflect a MAX-mediated mechanism and opposing influences of HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α has opposing actions to HIF2α. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes.
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Project description:Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To establish whether PPGL phenotypic differences reflect a MAX-mediated mechanism and opposing influences of HIF2α and HIF1α, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α has opposing actions to HIF2α. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes.
2014-09-18 | GSE50941 | GEO