Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen se...Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.展开更多
Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation...Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.展开更多
目的分析中医药调节低氧诱导因子(HIF)表达相关研究文献,了解该领域研究脉络、热点和发展趋势。方法计算机检索中国知识资源总库(CNKI)、中文科技期刊数据库(VIP)、中国学术期刊数据库(万方数据)、Web of Science 2011年1月1日-2020年12...目的分析中医药调节低氧诱导因子(HIF)表达相关研究文献,了解该领域研究脉络、热点和发展趋势。方法计算机检索中国知识资源总库(CNKI)、中文科技期刊数据库(VIP)、中国学术期刊数据库(万方数据)、Web of Science 2011年1月1日-2020年12月31日收录的中医药调节HIF表达相关中、英文文献。采用CiteSpace5.8R2和VOSviewer1.6.17软件绘制相关文献的作者合作视图和关键词的共现、聚类、突现及时间线知识图谱,并进行分析。结果经筛选,共纳入中文文献3779篇,英文文献316篇。中医药调节HIF表达的中文和英文文献发文量分别集中在2017年和2020年。关键词共现分析表明,中文文献高频关键词有“动物模型”“氧化应激”“实验药理”“缺氧诱导因子-1α”“血管内皮生长因子”“细胞凋亡”“hif-1α”“大鼠”“网络药理学”“血管新生”等,英文文献高频关键词有“network pharmacology”“expression”“angiogenesis”“apoptosis”“hypoxia”“inflammation”“activation”“hif-1 alpha”“cells”“oxidative stress”等。关键词聚类分析显示,中、英文文献各得到11个有效聚类。关键词突现分析显示,中、英文文献各得到19个突现词。结论近年来国内外中医药调节HIF表达研究热度持续上升,中医药对HIF干预手段不断更新、涉及疾病范围不断扩大,尤其在炎症和肿瘤方面。展开更多
Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated wi...Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.展开更多
Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
Hypoxia-inducible factor(HIF)is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes.HIF is frequen...Hypoxia-inducible factor(HIF)is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes.HIF is frequently upregulated in solid tumors,and the overexpression of HIF can promote tumor progression or aggressiveness by blood vessel architecture and altering cellular metabolism.In this review,we focused on the pivotal role of HIF in tumor angiogenesis and energy metabolism.Furthermore,we also emphasized the possibility of HIF pathway as a potential therapeutic target in cancer.展开更多
Small ubiquitin-like modifier protein （SUMO） modification is a highly dynamic process, catalyzed by SUMO- specific activating （El）, conjugating （E2） and ligating （E3） enzymes, and reversed by a family of SUMO-...Small ubiquitin-like modifier protein （SUMO） modification is a highly dynamic process, catalyzed by SUMO- specific activating （El）, conjugating （E2） and ligating （E3） enzymes, and reversed by a family of SUMO-specific proteases （SENPs）. There are six members of the human SENP family, and each SENP has different cellular locations and substrate specificities. However, the precise roles of SENPs in cellular processes have not been elucidated to date. This brief review will focus on recent advances pertaining to the identified targets of SENP 1 and its potential role in prostate cancer.展开更多
AIM： To investigate the anticancer activity of DT-13 under normoxia and determine the underlying mechanisms of action. METHODS： MDA-MB-435 cell proliferation, migration, and adhesion were performed to assess the ant...AIM： To investigate the anticancer activity of DT-13 under normoxia and determine the underlying mechanisms of action. METHODS： MDA-MB-435 cell proliferation, migration, and adhesion were performed to assess the anticancer activity of DT-13, a saponin from Ophiopogonjaponicus, in vitro. In addition, the effects of DT-13 on tumor growth and metastasis in vivo were evaluated by orthotopic implantation of MDA-MB-435 cells into nude mice; mRNA levels of vascular endothelial growth factor （VEGF）, C-C chemokine receptor type 5 （CCR5） and hypoxia-inducible factor 1a （HIF-1a） were evaluated by real-time quantitative PCR; and CCR5 protein levels were detected by Western blot assay. RESULTS： At 0.01 to 1 umol·L -1, DT-13 inhibited MDA-MB-435 cell proliferation, migration, and adhesion significantly in vitro. DT-13 reduced VEGF and CCR5 mRNAs, and decreased CCR5 protein expression by down-regulating HIF-1 a. In addition, DT-13 inhibited MDA-MB-435 cell lung metastasis, and restricted tumor growth slightly in vivo. CONCLUSION： DT-13 inhibited MDA-MB-435 cell proliferation, adhesion, and migration in vitro, and lung metastasis in vivo by reducing VEGF, CCR5, and HIF-la expression.展开更多
基金supported by funding from Cancer Prevention & Research Institute of Texas (CPRIT, RR140012)V Foundation (V2015-2022)+1 种基金Sabin Family Foundation Fellowship at MD Anderson (2016-00052285)generous support from the McNair Foundation
文摘Hypoxia acts as an important regulator of physiological and pathological processes. Hypoxia inducible factors(HIFs) are the central players involved in the cellular adaptation to hypoxia and are regulated by oxygen sensing EGLN prolyl hydroxylases.Hypoxia affects many aspects of cellular growth through both redox effects and through the stabilization of HIFs. The HIF isoforms likely have differential effects on tumor growth via alteration of metabolism, growth, and self-renewal and are likely highly context-dependent. In some tumors such as renal cell carcinoma, the EGLN/HIF axis appears to drive tumorigenesis,while in many others HIF1 and HIF2 may actually have a tumor suppressive role. An emerging role of HIF biology is its effects on the tumor microenvironment. The EGLN/HIF axis plays a key role in regulating the function of the various components of the tumor microenvironment, which include cancer-associated fibroblasts, endothelial cells, immune cells, and the extracellular matrix(ECM). Here, we discuss hypoxia and the diverse roles of HIFs in the setting of tumorigenesis and the maintenance of the tumor microenvironment as well as possible future directions of the field.
基金supported by the National Institute of Dental and Craniofacial Research(NIDCR)the National Center for Research Resources(NCRR)of the National Institutes of Health(NIH)under award numbers R21DE023178,R01DE024796,and S10RR027553
文摘Hypoxia（low oxygen level） is an important feature during infections and affects the host defence mechanisms. The host has evolved specific responses to address hypoxia, which are strongly dependent on the activation of hypoxia-inducible factor 1（HIF-1）.Hypoxia interferes degradation of HIF-1 alpha subunit（HIF-1α）, leading to stabilisation of HIF-1α, heterodimerization with HIF-1 beta subunit（HIF-1β） and subsequent activation of HIF-1 pathway. Apical periodontitis（periapical lesion） is a consequence of endodontic infection and ultimately results in destruction of tooth-supporting tissue, including alveolar bone. Thus far, the role of HIF-1 in periapical lesions has not been systematically examined. In the present study, we determined the role of HIF-1 in a wellcharacterised mouse periapical lesion model using two HIF-1α-activating strategies, dimethyloxalylglycine（DMOG） and adenovirusinduced constitutively active HIF-1α（CA-HIF1 A）. Both DMOG and CA-HIF1 A attenuated periapical inflammation and tissue destruction. The attenuation in vivo was associated with downregulation of nuclear factor-κappa B（NF-κB） and osteoclastic gene expressions. These two agents also suppressed NF-κB activation and subsequent production of proinflammatory cytokines by macrophages. Furthermore, activation of HIF-1α by DMOG specifically suppressed lipopolysaccharide-stimulated macrophage differentiation into M1 cells, increasing the ratio of M2 macrophages against M1 cells. Taken together, our data indicated that activation of HIF-1 plays a protective role in the development of apical periodontitis via downregulation of NF-κB, proinflammatory cytokines, M1 macrophages and osteoclastogenesis.
文摘Hypoxia is a common phenomenon in hepatocellular carcinoma （HCC）. Hypoxia stabilizes transcription factor, hypoxia-inducible factor （HIF）, to activate gene transcription. Expression of HIF is closely associated with metastasis and poor prognosis in HCC. HIF mediates expression of genes that are involved in every step of HCC metastasis including epithelial-mesenchymal transition, invasion of the extracellular matrix, intravasation, extravasation, and secondary growth of the metastases. Because HIF is the central regulator of HCC metastasis, HIF inhibitors are attractive tools when used alone or as combined treatment to curb HCC metastasis. This review will summarize the current findings on the impact of hypoxia/HIF in HCC, with a particular focus on cancer metastasis.
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
基金Grant sponsor:National Nature Science Foundation of China,Grant number:81272960Key Research Program from Science and Technology Department of Hunan Province China,Grant number:2013WK2010 and 2014SK2015+3 种基金The fund of Tianqing liver disease researchThis work was supported by National Nature Science Foundation of China(81272960)Key Research Program from Science and Technology Department of Hunan Province,China(2013WK2010 and 2014SK2015)Key Research Program from Ministry of human Resources and Social Security of the People’s Republic of China(2016)176.
文摘Hypoxia-inducible factor(HIF)is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes.HIF is frequently upregulated in solid tumors,and the overexpression of HIF can promote tumor progression or aggressiveness by blood vessel architecture and altering cellular metabolism.In this review,we focused on the pivotal role of HIF in tumor angiogenesis and energy metabolism.Furthermore,we also emphasized the possibility of HIF pathway as a potential therapeutic target in cancer.
基金Studies in the author＇s laboratory were funded by startup funds from the Shanghai Jiao Tong University School of Medicine, National Natural Science Foundation of China （No. 30772462）. Most of the work described in this review was performed in Dr Edward Yeh＇s laboratory at the MD Anderson Cancer Center, Houston, TX, USA.
文摘Small ubiquitin-like modifier protein （SUMO） modification is a highly dynamic process, catalyzed by SUMO- specific activating （El）, conjugating （E2） and ligating （E3） enzymes, and reversed by a family of SUMO-specific proteases （SENPs）. There are six members of the human SENP family, and each SENP has different cellular locations and substrate specificities. However, the precise roles of SENPs in cellular processes have not been elucidated to date. This brief review will focus on recent advances pertaining to the identified targets of SENP 1 and its potential role in prostate cancer.
基金supported by the National Natural Science Foundation(Nos.81102853,81071841)the 2011’Program for Excellent Scientific and Technological Innovation Team of Jiangsu Higher Education
文摘AIM： To investigate the anticancer activity of DT-13 under normoxia and determine the underlying mechanisms of action. METHODS： MDA-MB-435 cell proliferation, migration, and adhesion were performed to assess the anticancer activity of DT-13, a saponin from Ophiopogonjaponicus, in vitro. In addition, the effects of DT-13 on tumor growth and metastasis in vivo were evaluated by orthotopic implantation of MDA-MB-435 cells into nude mice; mRNA levels of vascular endothelial growth factor （VEGF）, C-C chemokine receptor type 5 （CCR5） and hypoxia-inducible factor 1a （HIF-1a） were evaluated by real-time quantitative PCR; and CCR5 protein levels were detected by Western blot assay. RESULTS： At 0.01 to 1 umol·L -1, DT-13 inhibited MDA-MB-435 cell proliferation, migration, and adhesion significantly in vitro. DT-13 reduced VEGF and CCR5 mRNAs, and decreased CCR5 protein expression by down-regulating HIF-1 a. In addition, DT-13 inhibited MDA-MB-435 cell lung metastasis, and restricted tumor growth slightly in vivo. CONCLUSION： DT-13 inhibited MDA-MB-435 cell proliferation, adhesion, and migration in vitro, and lung metastasis in vivo by reducing VEGF, CCR5, and HIF-la expression.
