{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T06:16:24Z","timestamp":1792131384124,"version":"4.4.0"},"reference-count":103,"publisher":"American Association for the Advancement of Science (AAAS)","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["12090052"],"award-info":[{"award-number":["12090052"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11874209"],"award-info":[{"award-number":["11874209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007847","name":"Natural Science Foundation of Jilin Province","doi-asserted-by":"publisher","award":["11574139"],"award-info":[{"award-number":["11574139"]}],"id":[{"id":"10.13039\/100007847","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11934008"],"award-info":[{"award-number":["11934008"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["spj.science.org"],"crossmark-restriction":true},"short-container-title":["Research"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>Graded hypoxia is a common microenvironment in malignant solid tumors. As a central regulator in the hypoxic response, hypoxia-inducible factor-1 (HIF-1) can induce multiple cellular processes including glycolysis, angiogenesis, and necroptosis. How cells exploit the HIF-1 pathway to coordinate different processes to survive hypoxia remains unclear. We developed an integrated model of the HIF-1\u03b1 network to elucidate the mechanism of cellular adaptation to hypoxia. By numerical simulations and bifurcation analysis, we found that HIF-1\u03b1 is progressively activated with worsening hypoxia due to the sequential deactivation of the hydroxylases prolyl hydroxylase domain enzymes and factor inhibiting HIF (FIH). Bistable switches control the activation and deactivation processes. As a result, glycolysis, immunosuppression, angiogenesis, and necroptosis are orderly elicited in aggravating hypoxia. To avoid the excessive accumulation of lactic acid during glycolysis, HIF-1\u03b1 induces monocarboxylate transporter and carbonic anhydrase 9 sequentially to export intracellular hydrogen ions, facilitating tumor cell survival. HIF-1\u03b1-induced miR-182 facilitates vascular endothelial growth factor production to promote angiogenesis under moderate hypoxia. The imbalance between accumulation and removal of lactic acid in severe hypoxia may result in acidosis and induce cell necroptosis. In addition, the deactivation of FIH results in the destabilization of HIF-1\u03b1 in anoxia. Collectively, HIF-1\u03b1 orchestrates the adaptation of tumor cells to hypoxia by selectively inducing its targets according to the severity of hypoxia. Our work may provide clues for tumor therapy by targeting the HIF-1 pathway.<\/jats:p>","DOI":"10.34133\/research.0651","type":"journal-article","created":{"date-parts":[[2025,3,13]],"date-time":"2025-03-13T16:53:17Z","timestamp":1741884797000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":21,"title":["Progressive Deactivation of Hydroxylases Controls Hypoxia-Inducible Factor-1\u03b1-Coordinated Cellular Adaptation to Graded Hypoxia"],"prefix":"10.34133","volume":"8","author":[{"given":"Ping","family":"Wang","sequence":"first","affiliation":[{"name":"Kuang Yaming Honors School, \rNanjing University, Nanjing 210023, China."},{"name":"Key Laboratory of High Performance Scientific Computation, School of Science, \rXihua University, Chengdu 610039, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-1236","authenticated-orcid":true,"given":"Xiao-Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Kuang Yaming Honors School, \rNanjing University, Nanjing 210023, China."},{"name":"Institute of Brain Sciences, \rNanjing University, Nanjing 210093, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-8518","authenticated-orcid":true,"given":"Feng","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Brain Sciences, \rNanjing University, Nanjing 210093, China."},{"name":"National Laboratory of Solid State Microstructures and Department of Physics, \rNanjing University, Nanjing 210093, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5441-0302","authenticated-orcid":true,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Brain Sciences, \rNanjing University, Nanjing 210093, China."},{"name":"National Laboratory of Solid State Microstructures and Department of Physics, \rNanjing University, Nanjing 210093, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2025,4]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3726"},{"issue":"7495","key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/nature13034","article-title":"Direct measurement of local oxygen concentration in the bone marrow of live animals","volume":"508","author":"Spencer JA","year":"2014","unstructured":"Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508(7495):269\u2013273.","journal-title":"Nature"},{"issue":"13","key":"e_1_3_4_4_2","first-page":"5262","article-title":"Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density","volume":"61","author":"Beasley NJ","year":"2001","unstructured":"Beasley NJ, Wykoff CC, Watson PH, Leek R, Turley H, Gatter K, Pastorek J, Cox GJ, Ratcliffe P, Harris AL. Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density. Cancer Res. 2001;61(13):5262\u20135267.","journal-title":"Cancer Res"},{"issue":"1","key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"22","DOI":"10.7150\/jca.12917","article-title":"Linearly patterned programmed cell necrosis induced by chronic hypoxia plays a role in melanoma angiogenesis","volume":"7","author":"Zhao X","year":"2016","unstructured":"Zhao X, Sun B, Liu Y, Zhang D, Liu Z, Zhao X, Gu Q, Han C, Dong X, Che N, et al. Linearly patterned programmed cell necrosis induced by chronic hypoxia plays a role in melanoma angiogenesis. J Cancer. 2016;7(1):22\u201331.","journal-title":"J Cancer"},{"issue":"2","key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH693>3.0.CO;2-R","article-title":"\u2018Invading edge vs. inner\u2019 (edvin) patterns of vascularization: An interplay between angiogenic and vascular survival factors defines the clinical behaviour of non-small cell lung cancer","volume":"192","author":"Giatromanolaki A","year":"2000","unstructured":"Giatromanolaki A, Koukourakis MI, Sivridis E, O\u2019Byrne K, Gatter KC, Harris AL. \u2018Invading edge vs. inner\u2019 (edvin) patterns of vascularization: An interplay between angiogenic and vascular survival factors defines the clinical behaviour of non-small cell lung cancer. J Pathol. 2000;192(2):140\u2013149.","journal-title":"J Pathol"},{"issue":"4","key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/adt.2014.573","article-title":"Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors","volume":"12","author":"Edmondson R","year":"2014","unstructured":"Edmondson R, Broglie JJ, Adcock AF, Yang L. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol. 2014;12(4):207\u2013218.","journal-title":"Assay Drug Dev Technol"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4405"},{"issue":"12","key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"5510","DOI":"10.1073\/pnas.92.12.5510","article-title":"Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension","volume":"92","author":"Wang GL","year":"1995","unstructured":"Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci. 1995;92(12):5510\u20135514.","journal-title":"Proc Natl Acad Sci"},{"issue":"2","key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0955-0674(00)00194-0","article-title":"HIF-1 and mechanisms of hypoxia sensing","volume":"13","author":"Semenza GL","year":"2001","unstructured":"Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 2001;13(2):167\u2013171.","journal-title":"Curr Opin Cell Biol"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1187"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1366"},{"issue":"3","key":"e_1_3_4_13_2","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1042\/BJ20040620","article-title":"Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-\u03b1-prolyl-4-hydroxylases","volume":"381","author":"Marxsen JH","year":"2004","unstructured":"Marxsen JH, Stengel P, Doege K, Heikkinen P, Jokilehto T, Wagner T, Jelkmann W, Jaakkola P, Metzen E. Hypoxia-inducible factor-1 (HIF-1) promotes its degradation by induction of HIF-\u03b1-prolyl-4-hydroxylases. Biochem J. 2004;381(Pt 3):761\u2013767.","journal-title":"Biochem J"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.924501"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2009.03.009"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M312254200"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1383-6"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-018-9600-2"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01276-10"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.06.035"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"12495","DOI":"10.1038\/srep12495","article-title":"Hypoxia-inducible miR-182 enhances HIF1\u03b1 signaling via targeting PHD2 and FIH1 in prostate cancer","volume":"5","author":"Li Y","year":"2015","unstructured":"Li Y, Zhang D, Wang X, Yao X, Ye C, Zhang S, Wang H, Chang C, Xia H, Wang YC, et al. Hypoxia-inducible miR-182 enhances HIF1\u03b1 signaling via targeting PHD2 and FIH1 in prostate cancer. Sci Rep. 2015;5:12495.","journal-title":"Sci Rep"},{"issue":"1","key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13046-020-1535-y","article-title":"The interplay between HIF-1\u03b1 and noncoding RNAs in cancer","volume":"39","author":"Peng X","year":"2020","unstructured":"Peng X, Gao H, Xu R, Wang H, Mei J, Liu C. The interplay between HIF-1\u03b1 and noncoding RNAs in cancer. J Exp Clin Cancer Res. 2020;39(1):27.","journal-title":"J Exp Clin Cancer Res"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"460","DOI":"10.3389\/fendo.2018.00460","article-title":"HIF-1, metabolism, and diabetes in the embryonic and adult heart","volume":"9","author":"Cerychova R","year":"2018","unstructured":"Cerychova R, Pavlinkova G. HIF-1, metabolism, and diabetes in the embryonic and adult heart. Front Endocrinol. 2018;9:460.","journal-title":"Front Endocrinol"},{"issue":"8","key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"E893","DOI":"10.1152\/ajpendo.00484.2013","article-title":"Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival","volume":"306","author":"Makanji Y","year":"2014","unstructured":"Makanji Y, Tagler D, Pahnke J, Shea LD, Woodruff TK. Hypoxia-mediated carbohydrate metabolism and transport promote early-stage murine follicle growth and survival. Am J Physiol Endocrinol Metab. 2014;306(8):E893.","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2468"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.02.002"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4564"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2006.8.1625"},{"issue":"7","key":"e_1_3_4_30_2","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1158\/0008-5472.CAN-22-2553","article-title":"CD73-dependent adenosine signaling through Adora2b drives immunosuppression in ductal pancreatic cancer","volume":"83","author":"Faraoni EY","year":"2023","unstructured":"Faraoni EY, Singh K, Chandra V, le Roux O, Dai Y, Sahin I, O\u2019Brien BJ, Strickland LN, Li L, Vucic E, et al. CD73-dependent adenosine signaling through Adora2b drives immunosuppression in ductal pancreatic cancer. Cancer Res. 2023;83(7):1111\u20131127.","journal-title":"Cancer Res"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq045"},{"issue":"11","key":"e_1_3_4_32_2","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1038\/nrc1478","article-title":"Why do cancers have high aerobic glycolysis?","volume":"4","author":"Gatenby RA","year":"2004","unstructured":"Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891\u2013899.","journal-title":"Nat Rev Cancer"},{"issue":"2","key":"e_1_3_4_33_2","first-page":"453","article-title":"Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release","volume":"39","author":"Goetze K","year":"2011","unstructured":"Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA, Mueller-Klieser W. Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol. 2011;39(2):453\u2013463.","journal-title":"Int J Oncol"},{"issue":"1","key":"e_1_3_4_34_2","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12935-014-0129-1","article-title":"Acidic extracellular pH promotes epithelial mesenchymal transition in Lewis lung carcinoma model","volume":"14","author":"Suzuki A","year":"2014","unstructured":"Suzuki A, Maeda T, Baba Y, Shimamura K, Kato Y. Acidic extracellular pH promotes epithelial mesenchymal transition in Lewis lung carcinoma model. Cancer Cell Int. 2014;14(1):129.","journal-title":"Cancer Cell Int"},{"issue":"4","key":"e_1_3_4_35_2","first-page":"C1172","article-title":"Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension","volume":"271","author":"Jiang BH","year":"1996","unstructured":"Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Phys. 1996;271(4):C1172\u2013C1180.","journal-title":"Am J Phys"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.03087"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.500405"},{"issue":"6","key":"e_1_3_4_38_2","first-page":"1454","article-title":"A dynamic model of the hypoxia-inducible factor 1 \u03b1 (HIF-1 \u03b1) network","volume":"126","author":"Nguyen LK","year":"2013","unstructured":"Nguyen LK, Cavadas MAS, Scholz CC, Fitzpatrick SF, Bruning U, Cummins EP, Tambuwala MM, Manresa MC, Kholodenko BN, Taylor CT, et al. A dynamic model of the hypoxia-inducible factor 1 \u03b1 (HIF-1 \u03b1) network. J Cell Sci. 2013;126(6):1454\u20131463.","journal-title":"J Cell Sci"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.00318"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13050988"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206955200"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.10.6922"},{"issue":"8","key":"e_1_3_4_43_2","first-page":"1785","article-title":"MiR-182 promotes proliferation and invasion and elevates the HIF-1\u03b1 -VEGF-A axis in breast cancer cells by targeting FBXW7","volume":"6","author":"Chiang CH","year":"2016","unstructured":"Chiang CH, Chu PY, Hou MF, Hung WC. MiR-182 promotes proliferation and invasion and elevates the HIF-1\u03b1 -VEGF-A axis in breast cancer cells by targeting FBXW7. Am J Cancer Res. 2016;6(8):1785\u20131798.","journal-title":"Am J Cancer Res"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2013.1371"},{"issue":"2","key":"e_1_3_4_45_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1002\/iub.572","article-title":"The monocarboxylate transporter family\u2014Role and regulation","volume":"64","author":"Halestrap AP","year":"2012","unstructured":"Halestrap AP, Wilson MC. The monocarboxylate transporter family\u2014Role and regulation. IUBMB Life. 2012;64(2):109\u2013119.","journal-title":"IUBMB Life"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04871"},{"issue":"3","key":"e_1_3_4_47_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s00424-009-0750-3","article-title":"Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes","volume":"459","author":"P\u00e9rez de Heredia F","year":"2010","unstructured":"P\u00e9rez de Heredia F, Wood IS, Trayhurn P. Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes. Pflugers Arch. 2010;459(3):509\u2013518.","journal-title":"Pflugers Arch"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(03)01179-7"},{"issue":"8","key":"e_1_3_4_49_2","doi-asserted-by":"crossref","first-page":"6183","DOI":"10.1074\/jbc.M110978200","article-title":"Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect","volume":"277","author":"Minchenko A","year":"2002","unstructured":"Minchenko A, Leshchinsky I, Opentanova I, Sang N, Srinivas V, Armstead V, Caro J. Hypoxia-inducible factor-1-mediated expression of the 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3 (PFKFB3) gene. Its possible role in the Warburg effect. J Biol Chem. 2002;277(8):6183\u20136187.","journal-title":"J Biol Chem"},{"issue":"12","key":"e_1_3_4_50_2","doi-asserted-by":"crossref","first-page":"777","DOI":"10.18632\/oncoscience.109","article-title":"Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question","volume":"1","author":"Alfarouk KO","year":"2014","unstructured":"Alfarouk KO, Verduzco D, Rauch C, Muddathir AK, Bashir AHH, Elhassan GO, Ibrahim ME, Orozco JDP, Cardone RA, Reshkin SJ, et al. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience. 2014;1(12):777\u2013802.","journal-title":"Oncoscience"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.570041","article-title":"Targeting hypoxia-A2A adenosinergic immunosuppression of antitumor T cells during cancer immunotherapy","volume":"11","author":"Steingold JM","year":"2020","unstructured":"Steingold JM, Hatfield SM. Targeting hypoxia-A2A adenosinergic immunosuppression of antitumor T cells during cancer immunotherapy. Front Immunol. 2020;11: 570041.","journal-title":"Front Immunol"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ade5111"},{"key":"e_1_3_4_53_2","doi-asserted-by":"crossref","first-page":"1328565","DOI":"10.3389\/fimmu.2024.1328565","article-title":"Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome","volume":"15","author":"Figarella K","year":"2024","unstructured":"Figarella K, Kim J, Ruan W, Mills T, Eltzschig HK, Yuan X. Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome. Front Immunol. 2024;15:1328565.","journal-title":"Front Immunol"},{"key":"e_1_3_4_54_2","doi-asserted-by":"crossref","first-page":"1163585","DOI":"10.3389\/fimmu.2023.1163585","article-title":"The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer","volume":"14","author":"Strickland LN","year":"2023","unstructured":"Strickland LN, Faraoni EY, Ruan W, Yuan X, Eltzschig HK, Bailey-Lundberg JM. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer. Front Immunol. 2023;14:1163585.","journal-title":"Front Immunol"},{"issue":"4","key":"e_1_3_4_55_2","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.31557\/APJCP.2022.23.4.1239","article-title":"The prognostic role of CD73\/A2AR expression and tumor immune response in periampullary carcinoma subtypes","volume":"23","author":"Sweed D","year":"2022","unstructured":"Sweed D, Taha M, Abd Elhamed S, El Dein Mohamed AS. The prognostic role of CD73\/A2AR expression and tumor immune response in periampullary carcinoma subtypes. Asian Pac J Cancer Prev. 2022;23(4):1239\u20131246.","journal-title":"Asian Pac J Cancer Prev"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.651547"},{"issue":"7","key":"e_1_3_4_57_2","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1161\/01.RES.0000144805.11519.1e","article-title":"Reversible connexin 43 dephosphorylation during hypoxia and reoxygenation is linked to cellular ATP levels","volume":"95","author":"Turner MS","year":"2004","unstructured":"Turner MS, Haywood GA, Andreka P, You L, Martin PE, Evans WH, Webster KA, Bishopric NH. Reversible connexin 43 dephosphorylation during hypoxia and reoxygenation is linked to cellular ATP levels. Circ Res. 2004;95(7):726\u2013733.","journal-title":"Circ Res"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17003"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002801"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000002288"},{"issue":"3","key":"e_1_3_4_61_2","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.4049\/jimmunol.1100593","article-title":"Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury","volume":"192","author":"Eckle T","year":"2014","unstructured":"Eckle T, Kewley EM, Brodsky KS, Tak E, Bonney S, Gobel M, Anderson D, Glover LE, Riegel AK, Colgan SP, et al. Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol. 2014;192(3):1249\u20131256.","journal-title":"J Immunol"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/367576a0"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200302047"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells8050471"},{"key":"e_1_3_4_65_2","doi-asserted-by":"crossref","first-page":"18875","DOI":"10.1038\/s41598-021-98381-2","article-title":"Glycolysis-related gene expression profiling serves as a novel prognosis risk predictor for human hepatocellular carcinoma","volume":"11","author":"Zhang L","year":"2021","unstructured":"Zhang L, Li Y, Dai Y, Wang D, Wang X, Cao Y, Liu W, Tao Z. Glycolysis-related gene expression profiling serves as a novel prognosis risk predictor for human hepatocellular carcinoma. Sci Rep. 2021;11:18875.","journal-title":"Sci Rep"},{"issue":"8","key":"e_1_3_4_66_2","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1038\/sj.bjc.6600215","article-title":"The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer","volume":"86","author":"Turner KJ","year":"2002","unstructured":"Turner KJ, Crew JP, Wykoff CC, Watson PH, Poulsom R, Pastorek J, Ratcliffe PJ, Cranston D, Harris AL. The hypoxia-inducible genes VEGF and CA9 are differentially regulated in superficial vs invasive bladder cancer. Br J Cancer. 2002;86(8):1276\u20131282.","journal-title":"Br J Cancer"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.6.1834-1843.2002"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003451"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.22214"},{"issue":"27","key":"e_1_3_4_70_2","doi-asserted-by":"crossref","first-page":"42805","DOI":"10.18632\/oncotarget.8715","article-title":"Dysregulation and functional roles of miR-183-96-182 cluster in cancer cell proliferation, invasion and metastasis","volume":"7","author":"Ma Y","year":"2016","unstructured":"Ma Y, Liang AJ, Fan YP, Huang YR, Zhao XM, Sun Y, Chen XF. Dysregulation and functional roles of miR-183-96-182 cluster in cancer cell proliferation, invasion and metastasis. Oncotarget. 2016;7(27):42805\u201342825.","journal-title":"Oncotarget"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.257394.114"},{"issue":"1","key":"e_1_3_4_72_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/mc.22741","article-title":"MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the met gene","volume":"57","author":"Li Y","year":"2018","unstructured":"Li Y, Zhang H, Li Y, Zhao C, Fan Y, Liu J, Li X, Liu H, Chen J. MiR-182 inhibits the epithelial to mesenchymal transition and metastasis of lung cancer cells by targeting the met gene. Mol Carcinog. 2018;57(1):125\u2013136.","journal-title":"Mol Carcinog"},{"issue":"6","key":"e_1_3_4_73_2","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1038\/sj.onc.1208305","article-title":"Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2\u03b1 in von Hippel\u2013Lindau renal cell carcinoma","volume":"24","author":"Petrella BL","year":"2005","unstructured":"Petrella BL, Lohi J, Brinckerhoff CE. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2\u03b1 in von Hippel\u2013Lindau renal cell carcinoma. Oncogene. 2005;24(6):1043\u20131052.","journal-title":"Oncogene"},{"issue":"2","key":"e_1_3_4_74_2","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1152\/physiolgenomics.00041.2020","article-title":"miR-125 family regulates XIRP1 and FIH in response to myocardial infarction","volume":"52","author":"Williams AL","year":"2020","unstructured":"Williams AL, Khadka VS, Anagaran MCT, Lee K, Avelar A, Deng Y, Shohet RV. miR-125 family regulates XIRP1 and FIH in response to myocardial infarction. Physiol Genomics. 2020;52(2):358\u2013368.","journal-title":"Physiol Genomics"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01242-10"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000969"},{"issue":"7","key":"e_1_3_4_77_2","doi-asserted-by":"crossref","first-page":"e140300","DOI":"10.1172\/JCI140300","article-title":"Hypoxia-inducible factor\u20131\u03b1 \u2013dependent induction of miR122 enhances hepatic ischemia tolerance","volume":"131","author":"Ju C","year":"2021","unstructured":"Ju C, Wang M, Tak E, Kim B, Emontzpohl C, Yang Y, Yuan X, Kutay H, Liang Y, Hall DR, et al. Hypoxia-inducible factor\u20131\u03b1 \u2013dependent induction of miR122 enhances hepatic ischemia tolerance. J Clin Invest. 2021;131(7):e140300.","journal-title":"J Clin Invest"},{"key":"e_1_3_4_78_2","doi-asserted-by":"crossref","first-page":"8042","DOI":"10.1038\/s41467-024-52113-y","article-title":"HIF-2\u03b1-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis","volume":"15","author":"Czopik AK","year":"2024","unstructured":"Czopik AK, McNamee EN, Vaughn V, Huang X, Bang IH, Clark T, Wang Y, Ruan W, Nguyen T, Masterson JC, et al. HIF-2\u03b1-dependent induction of miR-29a restrains TH1 activity during T cell dependent colitis. Nat Commun. 2024;15:8042.","journal-title":"Nat Commun"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.15.5454-5468.2000"},{"issue":"4","key":"e_1_3_4_80_2","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/cdd.2008.185","article-title":"The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death","volume":"16","author":"Burton TR","year":"2009","unstructured":"Burton TR, Gibson SB. The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death Differ. 2009;16(4):515\u2013523.","journal-title":"Cell Death Differ"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18040687"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00166-09"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5344"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21082660"},{"issue":"11","key":"e_1_3_4_85_2","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1038\/s41388-018-0555-y","article-title":"Tissue necrosis and its role in cancer progression","volume":"38","author":"Karsch-Bluman A","year":"2019","unstructured":"Karsch-Bluman A, Feiglin A, Arbib E, Stern T, Shoval H, Schwob O, Berger M, Benny O. Tissue necrosis and its role in cancer progression. Oncogene. 2019;38(11):1920\u20131935.","journal-title":"Oncogene"},{"issue":"7","key":"e_1_3_4_86_2","doi-asserted-by":"crossref","DOI":"10.1002\/bies.202100029","article-title":"Tumor necrosis: A synergistic consequence of metabolic stress and inflammation","volume":"43","author":"Yee PP","year":"2021","unstructured":"Yee PP, Li W. Tumor necrosis: A synergistic consequence of metabolic stress and inflammation. BioEssays. 2021;43(7): e2100029.","journal-title":"BioEssays"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-018-0555-4"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-015-1997-z"},{"issue":"11","key":"e_1_3_4_89_2","doi-asserted-by":"crossref","first-page":"10961","DOI":"10.1007\/s11033-022-07802-6","article-title":"Acute vs. chronic vs. intermittent hypoxia in breast cancer: A review on its application in in\u00a0vitro research","volume":"49","author":"Liu Q","year":"2022","unstructured":"Liu Q, Palmgren VAC, Danen EH, Le D\u00e9v\u00e9dec SE. Acute vs. chronic vs. intermittent hypoxia in breast cancer: A review on its application in in\u00a0vitro research. Mol Biol Rep. 2022;49(11):10961\u201310973.","journal-title":"Mol Biol Rep"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.248"},{"issue":"1","key":"e_1_3_4_91_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1042\/bj20031299","article-title":"p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1)","volume":"380","author":"Schmid T","year":"2004","unstructured":"Schmid T, Zhou J, K\u00f6hl R, Br\u00fcne B. p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J. 2004;380(Pt 1):289\u2013295.","journal-title":"Biochem J"},{"key":"e_1_3_4_92_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.587493"},{"key":"e_1_3_4_93_2","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2021.762742","article-title":"Emerging roles of the tumor suppressor p53 in metabolism","volume":"9","author":"Yu L","year":"2022","unstructured":"Yu L, Wu M, Zhu G, Xu Y. Emerging roles of the tumor suppressor p53 in metabolism. Front Cell Dev Biol. 2022;9: 762742.","journal-title":"Front Cell Dev Biol"},{"issue":"18","key":"e_1_3_4_94_2","doi-asserted-by":"crossref","first-page":"2596\u20132611","DOI":"10.1002\/1873-3468.13525","article-title":"Modeling the regulation of p53 activation by HIF-1 upon hypoxia","volume":"593","author":"Wang P","year":"2019","unstructured":"Wang P, Guan D, Zhang XP, Liu F, Wang W. Modeling the regulation of p53 activation by HIF-1 upon hypoxia. FEBS Lett. 2019;593(18):2596\u20132611.","journal-title":"FEBS Lett"},{"key":"e_1_3_4_95_2","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2019.1613370"},{"issue":"3","key":"e_1_3_4_96_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/febs.13578","article-title":"NF-\u03baB and HIF crosstalk in immune responses","volume":"283","author":"D\u2019Ignazio L","year":"2015","unstructured":"D\u2019Ignazio L, Bandarra D, Rocha S. NF-\u03baB and HIF crosstalk in immune responses. FEBS J. 2015;283(3):413\u2013424.","journal-title":"FEBS J"},{"key":"e_1_3_4_97_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06905"},{"key":"e_1_3_4_98_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.151588598"},{"key":"e_1_3_4_99_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2019.10.060"},{"key":"e_1_3_4_100_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-023-00886-y"},{"issue":"6","key":"e_1_3_4_101_2","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1053\/j.ajkd.2015.12.020","article-title":"Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: A phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study","volume":"67","author":"Provenzano R","year":"2016","unstructured":"Provenzano R, Besarab A, Wright S, Dua S, Zeig S, Nguyen P, Poole L, Saikali KG, Saha G, Hemmerich S, et al. Roxadustat (FG-4592) versus epoetin alfa for anemia in patients receiving maintenance hemodialysis: A phase 2, randomized, 6- to 19-week, open-label, active-comparator, dose-ranging, safety and exploratory efficacy study. Am J Kidney Dis. 2016;67(6):912\u2013924.","journal-title":"Am J Kidney Dis"},{"issue":"10","key":"e_1_3_4_102_2","article-title":"Anemia and hypoxia impact on chronic kidney disease onset and progression: Review and updates","volume":"15","author":"Habas ES","year":"2023","unstructured":"Habas ES, Al Adab A, Arryes M, Alfitori G, Farfar K, Habas AM, Akbar RA, Rayani A, Habas E, Elzouki A. Anemia and hypoxia impact on chronic kidney disease onset and progression: Review and updates. Cureus. 2023;15(10): e46737.","journal-title":"Cureus"},{"key":"e_1_3_4_103_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010818-021637"},{"key":"e_1_3_4_104_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.153346"}],"container-title":["Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/spj.science.org\/doi\/pdf\/10.34133\/research.0651","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T15:48:29Z","timestamp":1743522509000},"score":1,"resource":{"primary":{"URL":"https:\/\/spj.science.org\/doi\/10.34133\/research.0651"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1]]},"references-count":103,"alternative-id":["10.34133\/research.0651"],"URL":"https:\/\/doi.org\/10.34133\/research.0651","relation":{},"ISSN":["2639-5274"],"issn-type":[{"value":"2639-5274","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1]]},"assertion":[{"value":"2024-12-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-26","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"0651"}}