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Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [human]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51081 | GEO | 2014/09/18

SECONDARY ACCESSION(S): PRJNA221143

REPOSITORIES: GEO

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Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [rat]

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).

2014-09-18 | E-GEOD-50941 | biostudies-arrayexpress

Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [rat]

2014-09-18 | GSE50941 | GEO

Opposing Effects of HIF1M-NM-1 and HIF2M-NM-1 on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [human]

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 HIF2M-NM-1 and HIF1M-NM-1, 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 Hif2M-NM-1, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1M-NM-1 has opposing actions to HIF2M-NM-1. These model systems explain the features observed in PPGLs due to mutations of MAX and other PPGL susceptibility genes. 88 samples (primary pheochromocytoma (PCC)/paraganglioma tumors) were hybridized onto a cDNA microarray in order to investigate possible heterogeneity within these tumors. This series of tumors is an expansion of GSE19422 that includes nine additional tumors to examine the role of MAX mutations in PCC/PGL.

2014-09-18 | E-GEOD-51081 | biostudies-arrayexpress

HIF1α/HIF2α-miR210-3p network promotes glioblastoma proliferation and tumorigenesis through EGFR-PI3K/AKT signaling pathway with a positive feedback

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.

2020-11-24 | GSE142719 | GEO

Project description:Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX

| PRJNA221147 | ENA

Rattus norvegicus

Project description:Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [rat]

| PRJNA219400 | ENA

Homo sapiens

Project description:Opposing Effects of HIF1α and HIF2α on Chromaffin Cell Phenotypic Features and Tumor Cell Proliferation: Insights from MAX [human]

| PRJNA221143 | ENA

Effects of HIF2α in renal cancer metastasis and sensitivity to repurposed drugs

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.

2021-08-11 | GSE153711 | GEO

miRNA expression in primary renal carcinomas, subgrouped based on HIF1α expression

Project description:Clear cell renal cell carcinoma (ccRCC), the most common type of renal cancer is often associated with inactivation of the tumor suppressor gene von-Hippel Lindau (VHL), leading to stable expression of hypoxia inducible factors, HIF1α and HIF2α. Although HIF1α functions as a tumor suppressor gene, majority of ccRCCs constitutively express HIF1α, stratifying VHL-deficient ccRCCs into groups which express either both HIF1α and HIF2α (H1H2) or HIF2α exclusively (H2). MicroRNA (miRNA) profiling performed in these two ccRCC subtypes to identify novel molecular mechanisms. ccRCCs were classified into H1H2 and H2 subtypes by immunohostochemical staining of H1F1α and H1F2α expression. Five H1H2 tumor samples and eight H2 tumor samples were used for the study. Matched adjacent normal renal tissues were used as respective controls.

2013-09-30 | E-GEOD-47582 | biostudies-arrayexpress

Combined epigenetic and differentiation-based treatment inhibits neuroblastoma tumor growth and links HIF2α to tumor suppression [array]

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.

2017-08-23 | GSE102994 | GEO

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