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Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis  [PDF]
Qian Zhang, Yan Chen, Bin Zhang, Bin Shi, Wenjun Weng, Zhipeng Chen, Nannan Guo, Yibing Hua, Lingjun Zhu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0070961
Abstract: Background HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis. Methods Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I 2, and funnel plot. Results Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M?) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR = 1.36, 95% CI = 1.12–1.64; TT+ TC vs. CC, OR = 1.39, 95% CI = 1.13–1.71; TT vs. TC+ CC, OR = 1.93, 95% CI = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis. Conclusions Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress.
Hypoxia-inducible factor-1α polymorphisms and TSC1/2 mutations are complementary in head and neck cancers
Carla Hebert, Kathleen Norris, Pallavi Parashar, Robert A Ord, Nikolaos G Nikitakis, John J Sauk
Molecular Cancer , 2006, DOI: 10.1186/1476-4598-5-3
Abstract: Denaturing high pressure liquid chromatography (DHPLC) analysis on PCR fragments in exon 12 of HIF-1alpha from 28 patients with OSCC revealed that 6 of 28 patients had mismatched heteroduplex patterns. Genomic DNA was extracted from peripheral blood leukocytes and direct sequencing showed that in 5 of the six cases these changes represented polymorphisms while, one case was a somatic mutation. Analyses of TSC1 and TSC2 revealed heteroduplexes in exons: TSC1 exon 17; TSC2 exons 36,40, and 41. The relative levels of HIF-1alpha were significantly greater for tumors possessing a HIF-1alpha polymorphism or mutation within exon 12, whereas tumors possessing a deletion or polymorphism in TSC1/TSC2 displayed a trend for higher levels of HIF-1alpha. Western blot analyses for HIF-1alpha, TSC1 and TSC2 in five SCC cell lines revealed high levels of HIF-1alpha in SCC cells possessing TSC1 and/or TSC2 mutations. Wild-type TSC2 cells targeted with siRNA to TSC2 exhibited increased levels of HIF-1alpha. Transfection of a HIF-1alpha mutant produced higher levels of HIF-1alpha in TSC1/TSC2 mutant cell lines than in wild type cells. TSC1/TSC2 mutant cell lines administered Rapamycin blocked S6 phorphorylation and diminished the levels of HIF-1alpha to those observed in cell lines with wild type TSC1/TSC2.Dysregulation of the TSC1/TSC2 complex by mutation compliments HIF-1α polymorphisms in the expression of HIF-1alpha in SCC of the head and neck, and may provide biomarkers to predict responses to specific therapies and overall disease prognosis.Hypoxia, a frequent effect of solid tumor growth in head and neck cancer and other cancers, serves to generate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cell-cycle control proteins. These cell-salvaging mechanisms can be carried out rapidly by a transcription factor that reacts to hypoxic conditions, the hypoxia-inducible factor-1 (HIF-1) [1]. HIF-1 is a heterodimer consisting of an α subunit and a β s
Polymorphisms in the hypoxia-inducible factor 1 alpha gene in Mexican patients with preeclampsia: A case-control study
Sonia Nava-Salazar, Elly N Sánchez-Rodríguez, C Mendoza-Rodríguez, Carlos Moran, Juan F Romero-Arauz, Marco A Cerbón
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-68
Abstract: Genomic DNA was isolated from 150 preeclamptic and 105 healthy pregnant women. Exon 12 of the HIF1A gene was amplified by PCR, and the genotypes of HIF1A were determined by DNA sequencing.In preeclamptic women and controls, the frequencies of the T allele for C1772T were 4.3 vs. 4.8%, and the frequencies of the A allele for G1790A were 0.0 vs. 0.5%, respectively. No significant differences were found between groups.The frequency of the C1772T and G1790A polymorphisms of the HIF1A gene is very low, and neither polymorphism is associated with the development of preeclampsia in the Mexican population.Preeclampsia (PE), a systemic syndrome occurring in pregnant women, is characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation and prior to 48 h postpartum [1-3]. It is the most important cause of morbidity and mortality in the mother-fetus binomial, affecting 5 to 8% of pregnant women worldwide. The actual percentage depends on the population studied and the definition of preeclampsia employed [4-6].One of the main characteristics of PE is an inadequate trophoblast invasion leading to an incomplete remodeling of the spiral artery, a reduction in utero-placental perfusion, and a state of placental hypoxia. It is considered that this condition can trigger widespread maternal endothelial dysfunction, and therefore the systemic manifestation of PE [7,8].HIF-1α is the major transducer of hypoxia signaling in several tissues, including human placenta [9,10]. Several studies suggest that hypoxia-inducible factor 1 alpha (HIF-1α), and two of the numerous genes that it regulates [11], soluble fms-like tyrosine kinase 1 (sFlT-1) and soluble endoglin (sEng) [12,13], are over-expressed in preeclamptic women and play a key role in the development of PE [14-17].It has been reported that a base change of C to T at 1772, or G to A at 1790 in exon 12 of the HIF1A gene can increase the transcriptional activity of this gene compared to the wild type isofor
An Association Study between Hypoxia Inducible Factor-1alpha (HIF-1α) Polymorphisms and Osteonecrosis  [PDF]
Georgia Chachami, Alkmini Kalousi, Loukia Papatheodorou, Aggeliki Lyberopoulou, Vasileios Nasikas, Keiji Tanimoto, George Simos, Konstantinos N. Malizos, Eleni Georgatsou
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079647
Abstract: Bone hypoxia resulting from impaired blood flow is the final pathway for the development of osteonecrosis (ON). The aim of this study was to evaluate if HIF-1α, the major transcription factor triggered by hypoxia, is genetically implicated in susceptibility to ON. For this we analyzed frequencies of three known HIF-1α polymorphisms: one in exon 2 (C111A) and two in exon 12 (C1772T and G1790A) and their association with ON in a Greek population. Genotype analysis was performed using PCR-RFLP and rare alleles were further confirmed with sequencing. We found that genotype and allele frequency of C1772T and G1790A SNP of HIF-1α (SNPs found in our cohort) were not significantly different in ON patients compared to control patients. Furthermore these SNPs could not be associated with the different subgroups of ON. At the protein level we observed that the corresponding mutations (P582S and A588T, respectively) are not significant for protein function since the activity, expression and localization of the mutant proteins is practically indistinguishable from wt in HEK293 and Saos-2 cells. These results suggest that these missense mutations in the HIF-1α gene are not important for the risk of developing ON.
The Association between Hypoxia-Inducible Factor-1 α Gene C1772T Polymorphism and Cancer Risk: A Meta-Analysis of 37 Case-Control Studies  [PDF]
Pengfei He, Qi Han, Jiajia Liu, Dongjuan Liu, Xin Zhao, Ting Hu, Lu Jiang, Hongxia Dan, Xin Zeng, Jing Li, Jiayi Wang, Qianming Chen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083441
Abstract: Background The possible association between HIF-1α C1772T polymorphism and cancer risk has been studied extensively. However, the results were controversial. In order to get a more precise conclusion of this association, a meta-analysis was performed. Methods A total of 10186 cases and 10926 controls in 37 case-control studies were included in this meta-analysis. Allele and genotypic differences between cases and controls were evaluated. Subgroup analysis by cancer site, ethnicity, source of controls and gender was performed. Results The T allele of HIF-1α gene C1772T was significantly associated with increased cancer risk in three genetic models: TT+CT vs.CC (dominant model OR=1.23, 95%CI=1.03-1.47), TT vs. CT+CC (recessive model OR=2.51, 95%CI=1.54-4.09), TT vs. CC (homozygote comparison OR=2.02, 95%CI=1.21-3.39).In subgroup analysis, the frequency of the T variant was found to be significantly increased in cervical cancer, pancreatic cancer, head and neck cancer, renal cell carcinoma, Asian and female subgroups. Conclusions Our meta-analysis suggests that the substitution of C allele with T at HIF-1α gene C1772T polymorphism is a risk factor of cancer, especially for cervical, head and neck cancer, pancreatic cancer and renal cell carcinoma. It is also a risk factor of cancer in Asian group as well as in female group.
Hypoxia-Inducible Factor in Thyroid Carcinoma  [PDF]
Natalie Burrows,Muhammad Babur,Julia Resch,Kaye J. Williams,Georg Brabant
Journal of Thyroid Research , 2011, DOI: 10.4061/2011/762905
Abstract: Intratumoural hypoxia (low oxygen tension) is associated with aggressive disease and poor prognosis. Hypoxia-inducible factor-1 is a transcription factor activated by hypoxia that regulates the expression of genes that promote tumour cell survival, progression, metastasis, and resistance to chemo/radiotherapy. In addition to hypoxia, HIF-1 can be activated by growth factor-signalling pathways such as the mitogen-activated protein kinases- (MAPK-) and phosphatidylinositol-3-OH kinases- (PI3K-) signalling cascades. Mutations in these pathways are common in thyroid carcinoma and lead to enhanced HIF-1 expression and activity. Here, we summarise current data that highlights the potential role of both hypoxia and MAPK/PI3K-induced HIF-1 signalling in thyroid carcinoma progression, metastatic characteristics, and the potential role of HIF-1 in thyroid carcinoma response to radiotherapy. Direct or indirect targeting of HIF-1 using an MAPK or PI3K inhibitor in combination with radiotherapy may be a new potential therapeutic target to improve the therapeutic response of thyroid carcinoma to radiotherapy and reduce metastatic burden. 1. Introduction The hypoxia-inducible factors (HIFs) are transcription factors that function under low oxygen tensions (hypoxia) and are, therefore, active in a number of diseases associated with low oxygen (O2) environments. These include ischemic disorders, atherosclerosis, and importantly cancer. HIF drives the survival and development of cancer cells by activating and repressing a multitude of genes that promote tumour cell survival, proliferation, invasion, and disease progression. As a result, hypoxia and HIF are associated with poor prognosis in many tumour types [1–3]. Hypoxia occurs in the majority of solid tumours, thus functional HIF is present in most tumour types indicating the importance of this signalling pathway in cancer. There is little known, however, about the role of HIF in thyroid carcinoma. Here, we summarise current literature that supports the potential significance of the HIF signalling pathway in progression and aggressiveness of thyroid carcinoma. Current data proposes that the HIF pathway may be a novel therapeutic target in reducing local tumour growth, metastatic burden, and resistance to chemo/radiotherapy. 2. Oxygen-Dependent Regulation of HIF-1 There are three known isoforms of HIF: HIF-1, 2, and 3. HIF-1 is expressed in all cells and is the most extensively researched, whereas the expression of the other isoforms is restricted to certain tissues. HIF-1 is a heterodimeric protein consisting of a
Hypoxia. Hypoxia, hypoxia inducible factor and myeloid cell function
Sarah R Walmsley, Edwin R Chilvers, Moira KB Whyte
Arthritis Research & Therapy , 2009, DOI: 10.1186/ar2632
Abstract: Despite the evolution of respiratory and cardiovascular systems in multicellular higher organisms, the presence of physiological oxygen gradients within and across tissues is well described. At sites of tissue injury and inflammation, oxygen gradients become exaggerated – and it is within relatively oxygen-deplete tissue environments that myeloid cells are required to migrate and function. These sites are typified by empyemas, healing wounds and inflamed joints, where oxygen tensions in the range of 0 to 3 kPa are well documented [1]. It therefore makes sense that myeloid cells have adapted to function at these sites of relative tissue hypoxia, although subversion of this response may also be important in the persistent inflammation associated with inflammatory arthritides, notably rheumatoid arthritis where tissue hypoxia is also linked to disease severity and progression.Hypoxia inducible factor (HIF), a transcriptional regulator of cellular responses to oxygen deprivation, plays a crucial role in the regulating myeloid cell function in hypoxia and in inflammation more broadly. The roles of HIF in regulating key myeloid cell functions and signalling pathways are discussed in the present review and are summarized in Figure 1.The major pathway for sustainable production of ATP utilizes oxygen in the mitochondrial electron transport system, the process known as oxidative phosphorylation. Within the majority of cells there is a critical intracellular oxygen partial pressure required for respiration (the Pasteur point), below which cells produce ATP through the nonoxygen-requiring process of glycolysis, resulting in the accumulation of lactic acid. The relative importance of these aerobic and anaerobic pathways is highly dependent on the cell systems examined. Myeloid cells are unique in that they have adapted to operate by anaerobic metabolism, even when transiting oxygen-replete areas, with neutrophils incorporating 85% of their glucose uptake into lactate even under
Expression of DDX3 Is Directly Modulated by Hypoxia Inducible Factor-1 Alpha in Breast Epithelial Cells  [PDF]
Mahendran Botlagunta,Balaji Krishnamachary,Farhad Vesuna,Paul T. Winnard Jr.,Guus M. Bol,Arvind H. Patel,Venu Raman
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017563
Abstract: DEAD box protein, DDX3, is aberrantly expressed in breast cancer cells ranging from weakly invasive to aggressive phenotypes and functions as an important regulator of cancer cell growth and survival. Here, we demonstrate that hypoxia inducible factor-1α is a transcriptional activator of DDX3 in breast cancer cells. Within the promoter region of the human DDX3 gene, we identified three putative hypoxia inducible factor-1 responsive elements. By luciferase reporter assays in combination with mutated hypoxia inducible factor-1 responsive elements, we determined that the hypoxia inducible factor-1 responsive element at position -153 relative to the translation start site is essential for transcriptional activation of DDX3 under hypoxic conditions. We also demonstrated that hypoxia inducible factor-1 binds to the DDX3 promoter and that the binding is specific, as revealed by siRNA against hypoxia inducible factor-1 and chromatin immunoprecipitation assays. Thus, the activation of DDX3 expression during hypoxia is due to the direct binding of hypoxia inducible factor-1 to hypoxia responsive elements in the DDX3 promoter. In addition, we observed a significant overlap in the protein expression pattern of hypoxia inducible factor-1α and DDX3 in MDA-MB-231 xenograft tumors. Taken together, our results demonstrate, for the first time, the role of DDX3 as a hypoxia-inducible gene that exhibits enhanced expression through the interaction of hypoxia inducible factor-1 with hypoxia inducible factor-1 responsive elements in its promoter region.
Hypoxia Regulates the Expression of the Neuromedin B Receptor through a Mechanism Dependent on Hypoxia-Inducible Factor-1α  [PDF]
Hyun-Joo Park, Mi-Kyoung Kim, Su-Ryun Kim, Soo-Kyung Bae, Moon-Kyoung Bae
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082868
Abstract: The neuromedin B receptor (NMB-R), a member of the mammalian bombesin receptor family, is frequently overexpressed in various tumors. In the present study, we found that exposure to hypoxic conditions increases the levels of NMBR mRNA and protein in breast cancer cells, which are tightly regulated by hypoxia-inducible factor-1α (HIF-1α). We confirmed the effect of HIF-1α on NMBR transcription by performing an NMBR promoter-driven reporter assay and then identified a functional hypoxia-responsive element (HRE) in the human NMBR promoter region. Further, the binding of HIF-1α to the NMBR promoter was corroborated by electrophoretic mobility shift and chromatin immunoprecipitation assays, which showed that HIF-1α specifically and directly bound to the NMBR promoter in response to hypoxia. Immunohistochemical analysis of a xenograft and a human breast cancer tissue array revealed a significant correlation between NMB-R and HIF-1α expression. Taken together, our findings indicate that hypoxia induces NMB-R expression through a novel mechanism to regulate HIF-1α expression in breast cancer cells.
Association between HIF1A P582S and A588T Polymorphisms and the Risk of Urinary Cancers: A Meta-Analysis  [PDF]
Dawei Li, Jikai Liu, Wenhua Zhang, Juchao Ren, Lei Yan, Hainan Liu, Zhonghua Xu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063445
Abstract: Purpose The hypoxia-inducible factor-1 alpha (HIF1A) plays a vital role in cancer initiation and progression. Previous studies have reported the existence of HIF1A P582S and A588T missense polymorphisms in renal, urothelial and prostatic carcinomas, however the effects remain conflicting. Therefore, we performed a meta-analysis to assess the association between these sites and the susceptibility of urinary cancers. Methods We searched the PubMed database without limits on language until Nov 25, 2012 for studies exploring the relationship of HIF1A P582S and A588T polymorphisms and urinary cancers. Still, article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of the associations between the two by RevMan 5.0 software. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 12.1 software. Results Overall, 11 individual case-control studies with 5195 cases and 5786 controls for P582S polymorphism, and 9 studies with 3482 cases and 4304 controls for A588T polymorphism were respectively included in the final meta-analysis. For HIF1A P582S polymorphism, individuals with TT genotype showed 1.60 fold higher risk than the others carrying CT or CC genotypes in Caucasian population (OR = 1.60, 95% CI = 1.09–2.33, Pheterogeneity = 0.11, P = 0.02). For HIF1A A588T polymorphism, the A allele was significantly correlated with higher urinary cancers risk in Asian population (OR = 1.41, 95% CI = 1.03–1.93, Pheterogeneity = 0.22, P = 0.03). Still, significant associations were found for prostate cancer in the allele and dominant models (OR = 1.46, 95% CI = 1.01–2.12, Pheterogeneity = 0.49, P = 0.04 and OR = 1.45, 95% CI = 1.00–2.12, Pheterogeneity = 0.50, P = 0.05). Conclusions The current findings suggest that HIF1A P582S polymorphism correlates with urinary cancers risk in Caucasian population, while A588T polymorphism may increase the risk of urinary cancers in Asian population and prostate cancer.
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