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Keiji Tanimoto - One of the best experts on this subject based on the ideXlab platform.
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the a allele at rs13419896 of EPAS1 is associated with enhanced expression and poor prognosis for non small cell lung cancer
PLOS ONE, 2015Co-Authors: Andika Chandra Putra, Hidetaka Eguchi, Kian Leong Lee, Yuko Yamane, Ewita Gustine, Takeshi Isobe, Masahiko Nishiyama, Keiko Hiyama, Lorenz Poellinger, Keiji TanimotoAbstract:Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC.
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association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female japanese non smokers
Journal of Thoracic Oncology, 2014Co-Authors: Shinichi Iwamoto, Andika Chandra Putra, Keiko Hiyama, Keiji Tanimoto, Yumi Nishio, Hiroshi Fuchita, Miki Ohe, Akihisa Sutani, Takashige Kuraki, Isao MurakamiAbstract:Introduction Hypoxia-inducible factor-2α (also called endothelial periodic acid–Schiff domain protein 1 [EPAS1]) seems to play an important role in some carcinogenesis, though there is no information on the relationship between single nucleotide polymorphism of EPAS1 and lung cancer development. The aim of this study was to explore a possible association of the EPAS1 gene rs4953354 polymorphism with susceptibility to lung cancer. Methods A case–control study of 346 patients with non–small-cell lung carcinoma (adenocarcinoma = 249, squamous cell carcinoma=97) and 247 healthy control subjects was carried out. A / G polymorphism within an intron 2 of the EPAS1 (rs4953354) was determined by direct sequencing. Results A frequency of lung adenocarcinoma patients with a minor allele G ( A / G or G / G genotype) at the rs4953354 was much higher than that of controls (odds ratio, 1.800; 95% confidence interval, 1.161–2.791; p = 0.008). This association was more evident when analyzed using female never-smokers (odds ratio, 3.31; 95% confidence interval, 1.21–9.01; p = 0.017). Mutations in epidermal growth factor receptor tended to be frequent in patients with G allele at the rs4953354, compared with those with other genotypes. Conclusion The EPAS1 rs4953354 may be a potentially susceptible marker for development of lung adenocarcinoma, especially in female never-smokers.
Andika Chandra Putra - One of the best experts on this subject based on the ideXlab platform.
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the a allele at rs13419896 of EPAS1 is associated with enhanced expression and poor prognosis for non small cell lung cancer
PLOS ONE, 2015Co-Authors: Andika Chandra Putra, Hidetaka Eguchi, Kian Leong Lee, Yuko Yamane, Ewita Gustine, Takeshi Isobe, Masahiko Nishiyama, Keiko Hiyama, Lorenz Poellinger, Keiji TanimotoAbstract:Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC.
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association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female japanese non smokers
Journal of Thoracic Oncology, 2014Co-Authors: Shinichi Iwamoto, Andika Chandra Putra, Keiko Hiyama, Keiji Tanimoto, Yumi Nishio, Hiroshi Fuchita, Miki Ohe, Akihisa Sutani, Takashige Kuraki, Isao MurakamiAbstract:Introduction Hypoxia-inducible factor-2α (also called endothelial periodic acid–Schiff domain protein 1 [EPAS1]) seems to play an important role in some carcinogenesis, though there is no information on the relationship between single nucleotide polymorphism of EPAS1 and lung cancer development. The aim of this study was to explore a possible association of the EPAS1 gene rs4953354 polymorphism with susceptibility to lung cancer. Methods A case–control study of 346 patients with non–small-cell lung carcinoma (adenocarcinoma = 249, squamous cell carcinoma=97) and 247 healthy control subjects was carried out. A / G polymorphism within an intron 2 of the EPAS1 (rs4953354) was determined by direct sequencing. Results A frequency of lung adenocarcinoma patients with a minor allele G ( A / G or G / G genotype) at the rs4953354 was much higher than that of controls (odds ratio, 1.800; 95% confidence interval, 1.161–2.791; p = 0.008). This association was more evident when analyzed using female never-smokers (odds ratio, 3.31; 95% confidence interval, 1.21–9.01; p = 0.017). Mutations in epidermal growth factor receptor tended to be frequent in patients with G allele at the rs4953354, compared with those with other genotypes. Conclusion The EPAS1 rs4953354 may be a potentially susceptible marker for development of lung adenocarcinoma, especially in female never-smokers.
Shi Han Chen - One of the best experts on this subject based on the ideXlab platform.
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EPAS1 and EGLN1 associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau.
Blood cells molecules & diseases, 2012Co-Authors: Norman E. Buroker, Xue Han Ning, Zhao Nian Zhou, Wei Jun Cen, Weizhong Zhu, C. Ronald Scott, Shi Han ChenAbstract:Abstract High altitude sickness (HAS) occurs among humans visiting or inhabiting high altitude environments. Genetic differences in the EPAS1 and EGLN1 genes have been found between lowland (Han) and highland (Tibetan) Chinese. Three SNPs within EPAS1 and EGLN1 were evaluated in Han and Tibetan patients with acute mountain sickness (AMS) and chronic mountain sickness (CMS). We compared 85 patients with AMS to 79 Han unaffected with mountain sickness (MS) as well as 45 CMS patients to 34 unaffected Tibetan subjects. The three SNPs studied were EPAS1 [ch2: 46441523 (hg18], EGLN1 (rs480902) and (rs516651). Direct sequencing was used to identify individual genotypes for the three SNPs. Age was found to be significantly associated with the EPAS1 SNP in the CMS patients while heart rate (HR) and oxygen saturation level of hemoglobin (SaO 2 ) were found to be significantly associated with the EGLN1 (rs480902) SNP in the Han patients with AMS. The individuals with CMS were found to diverge significantly for the EPAS1 SNP compared to their Tibetan control group as measured by genetic distance (0.123) indicating positive selection of the EPAS-G allele with age and illness. The EGLN1 (rs480902) SNP had a significant correlation with hematocrit (HCT), HR and SaO 2 in AMS patients. AMS and CMS were found to be significantly associated with the EPAS1 and EGLN1 SNPs compared to their Han and Tibetan control groups, respectively, indicating these nucleotide alterations have a physiological effect for the development of high altitude sickness.
Frédéric Debiève - One of the best experts on this subject based on the ideXlab platform.
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hif1a and EPAS1 potentiate hypoxia induced upregulation of inhibin alpha chain expression in human term cytotrophoblasts in vitro
Molecular Human Reproduction, 2017Co-Authors: Christophe Depoix, Corinne Hubinont, I De Selliers, Frédéric DebièveAbstract:Study Question Are hypoxia-inducible factors (HIF) responsible for the potentiation of inhibin alpha subunit (INHA) gene expression in primary cultures of human term cytotrophoblasts under low-oxygen tension? Summary Answer Both HIF1A and endothelial PAS domain protein 1 (EPAS1) are involved in the potentiation of INHA gene upregulation in cytotrophoblasts cultured under hypoxia. What Is Known Already During the in vitro differentiation of cytotrophoblasts into syncytiotrophoblasts under 21% O2, INHA expression increases. This expression is further increased when cells are cultured under low-oxygen tension (e.g. 2.5% O2). Moreover, in pregnancy-related diseases, such as pre-eclampsia or intrauterine growth restriction (IUGR), in which hypoxia is suspected to be responsible for the abnormal placental development, maternal serum concentration of inhibin A is elevated. Study Design, Size, Duration Cytotrophoblasts were isolated and purified from human term placentas (n = 6). Cells were cultured under 21% O2, and allowed to differentiate for 48 h. A first group of cells was treated for 16 h under 21% O2 with dimethyloxalylglycine (DMOG) or deferoxamine (DFX), molecules that mimic hypoxia by inhibiting HIF1 proteasomal degradation. Involvement of HIF1A and EPAS1 (also known as HIF2A), two HIF isoforms expressed in trophoblasts, was shown by treating another group of cells cultured under 2.5% O2 with specific inhibitors of HIF1A and EPAS1 for 16 h. INHA mRNA expression was assessed by real-time PCR and secreted inhibin A was quantified by ELISA. The role of HIF1A and EPAS1 in INHA transcriptional regulation was further confirmed by cotransfecting primary cytotrophoblasts with a luciferase reporter plasmid containing a 3.9 kb INHA promoter and plasmids allowing overexpression of HIF1A and EPAS1. Participants/Materials, Setting, Methods Placentas were obtained after vaginal or elective cesarean delivery from uncomplicated pregnancies at term (n≥ 4). The methods used were hormone measurements in the cell supernatants by enzyme-linked immunosorbent assay, real-time quantitative PCR, western blotting, immunofluorescence microscopy and transient transfection. Main Results and the Role of Chance HIF1 protein stabilization with DMOG and DFX increased 21% O2-induced INHA mRNA and protein upregulation (P < 0.05 versus control), while hypoxia-induced INHA upregulation was repressed by HIF1A and EPAS1 inhibitors (P < 0.05 versus control). In transfection experiments of primary term cytotrophoblasts, cloned INHA promoter transcriptional activity was increased by 2.5% O2 compared to 21% O2 (P < 0.05). Overexpression of both HIF1A and EPAS1 under 21% O2 increased cloned INHA transcriptional activity (P < 0.001 versus control). Large Scale Data Not applicable. Limitations, Reasons for Caution HIF1A and EPAS1 may regulate INHA expression by binding to an hypoxia-responsive element within the promoter, but we were unable to identify such an element. Inhibition of HIF1A and EPAS1 did not completely suppress upregulation of INHA expression suggesting that other transcription factors, not identified or studied here, are involved. Wider Implications of the Findings Our data suggest that the effect of HIF1 proteins on INHA gene promoter activity may be indirect. By demonstrating the role of HIF1A and especially EPAS1 in INHA gene upregulation under hypoxia, the results suggest that HIF1 proteins may become new therapeutic targets in the treatment of pregnancy-related diseases such as pre-eclampsia or IUGR. Study Funding/Competing Interest(s) This work was fully supported by 'Fetus for Life' charity. C. Depoix was supported by a fellowship 'Fonds de Recherche Clinique' from 'Fondation Saint-Luc', Belgium. The authors declare that there is no conflict of interest regarding the publication of this paper.
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HIF1A and EPAS1 mRNA and protein expression during in vitro culture of human primary term cytotrophoblasts and effect of oxygen tension on their expression
Reproductive Biology, 2016Co-Authors: Christophe Depoix, Olivier Flabat, Frédéric Debiève, Corinne HubinontAbstract:Abstract During the first trimester of pregnancy, placenta formation probably occurs in a low-oxygen environment necessary to protect cytotrophoblasts from oxidative stress and to allow proper gene regulation. Transcription factors involved in gene regulation under low oxygen tension are the hypoxia-inducible factors, mainly HIF1A, EPAS1 and their dimerization partner HIF1B. Little is known about their expression during in vitro culture of cytotrophoblasts under chronic hypoxia. We assessed HIF1A and EPAS1 expression in a 4-day in vitro culture of primary term cytotrophoblasts under 21% O2 and 2.5% O2. Copy numbers and relative mRNA expression were assessed by real-time quantitative polymerase chain reaction. Protein levels were quantified by immunoblot and densitometric analysis. In undifferentiated cytotrophoblasts, EPAS1 transcripts were four times more abundant than HIF1A transcripts (2.14e7 and 5e6 copies/μg total RNA, respectively). During cell culture, HIF1A mRNA expression increased after 24 h and then decreased to stay stable. The expression was even lower when cells were grown under 2.5% O2. EPAS1 mRNA expression increased during cytotrophoblast differentiation. The expression was higher when cells were under 21% O2 than when they were under 2.5% O2. Interestingly, HIF1A, but not EPAS1, was detected in the nuclei of undifferentiated cytotrophoblasts, and in the nuclei of cytotrophoblasts that grew under 21% O2. During cytotrophoblast differentiation, no variation in HIF1A protein levels was detected. To the contrary, EPAS1 protein level increased during differentiation, and oxygen tension had no effect on EPAS1 protein level. In conclusion, HIF1A and EPAS1 expression was not inhibited by chronic hypoxia during in vitro cytotrophoblast differentiation.
Keiko Hiyama - One of the best experts on this subject based on the ideXlab platform.
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the a allele at rs13419896 of EPAS1 is associated with enhanced expression and poor prognosis for non small cell lung cancer
PLOS ONE, 2015Co-Authors: Andika Chandra Putra, Hidetaka Eguchi, Kian Leong Lee, Yuko Yamane, Ewita Gustine, Takeshi Isobe, Masahiko Nishiyama, Keiko Hiyama, Lorenz Poellinger, Keiji TanimotoAbstract:Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC.
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association of EPAS1 gene rs4953354 polymorphism with susceptibility to lung adenocarcinoma in female japanese non smokers
Journal of Thoracic Oncology, 2014Co-Authors: Shinichi Iwamoto, Andika Chandra Putra, Keiko Hiyama, Keiji Tanimoto, Yumi Nishio, Hiroshi Fuchita, Miki Ohe, Akihisa Sutani, Takashige Kuraki, Isao MurakamiAbstract:Introduction Hypoxia-inducible factor-2α (also called endothelial periodic acid–Schiff domain protein 1 [EPAS1]) seems to play an important role in some carcinogenesis, though there is no information on the relationship between single nucleotide polymorphism of EPAS1 and lung cancer development. The aim of this study was to explore a possible association of the EPAS1 gene rs4953354 polymorphism with susceptibility to lung cancer. Methods A case–control study of 346 patients with non–small-cell lung carcinoma (adenocarcinoma = 249, squamous cell carcinoma=97) and 247 healthy control subjects was carried out. A / G polymorphism within an intron 2 of the EPAS1 (rs4953354) was determined by direct sequencing. Results A frequency of lung adenocarcinoma patients with a minor allele G ( A / G or G / G genotype) at the rs4953354 was much higher than that of controls (odds ratio, 1.800; 95% confidence interval, 1.161–2.791; p = 0.008). This association was more evident when analyzed using female never-smokers (odds ratio, 3.31; 95% confidence interval, 1.21–9.01; p = 0.017). Mutations in epidermal growth factor receptor tended to be frequent in patients with G allele at the rs4953354, compared with those with other genotypes. Conclusion The EPAS1 rs4953354 may be a potentially susceptible marker for development of lung adenocarcinoma, especially in female never-smokers.