{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:35:44Z","timestamp":1787027744300,"version":"build-2736575974"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T00:00:00Z","timestamp":1655424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Carlos III Health Institute","doi-asserted-by":"publisher","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Carlos III Health Institute","doi-asserted-by":"publisher","award":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Regional Development Fund\/European Social Fund \u201cA way to make Europe\u201d\/\u201dInvesting in your future\u201d","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}]},{"name":"European Regional Development Fund\/European Social Fund \u201cA way to make Europe\u201d\/\u201dInvesting in your future\u201d","award":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"]}]},{"name":"Network Biomedical Research Center\u2013Cancer (CIBERONC)","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}]},{"name":"Network Biomedical Research Center\u2013Cancer (CIBERONC)","award":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"]}]},{"name":"Spanish Group of Orphan and Infrequent Tumors (GETHI) and the PHEiPAS Association","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}]},{"name":"Spanish Group of Orphan and Infrequent Tumors (GETHI) and the PHEiPAS Association","award":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"]}]},{"name":"Spanish National Research Agency","award":["PI20\/01754"],"award-info":[{"award-number":["PI20\/01754"]}]},{"name":"Spanish National Research Agency","award":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2020-115401GB-I00\/AEI\/10.13039\/501100011033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Hypoxia-inducible factors (HIF) 2\u03b1 and 1\u03b1 are the major oxygen-sensing molecules in eukaryotic cells. HIF2\u03b1 has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2\u03b1 by immunohistochemistry in 62 PPGL\/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL\/HNPGL. We report that HIF2\u03b1 is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2\u03b1-regulated genes COX4I2 and ADORA2A. In contrast, HIF2\u03b1 and HIF2\u03b1-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2\u03b1 and HIF1\u03b1 protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1\u03b1-target genes are almost exclusively overexpressed in VHL-mutated HNPGL\/PPGL. Collectively, the data suggest that involvement of HIF2\u03b1 in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1\u03b1-independent.<\/jats:p>","DOI":"10.3390\/cancers14122986","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T05:25:11Z","timestamp":1655443511000},"page":"2986","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Differential HIF2\u03b1 Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3058-7231","authenticated-orcid":false,"given":"Luc\u00eda","family":"Celada","sequence":"first","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"CIBERONC (Network of Biomedical Research in Cancer), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Cubiella","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"CIBERONC (Network of Biomedical Research in Cancer), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9177-9408","authenticated-orcid":false,"given":"Jaime","family":"San-Juan-Guardado","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9217-3894","authenticated-orcid":false,"given":"Andr\u00e9s","family":"San Jos\u00e9 Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Vald\u00e9s","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"Department of Internal Medicine, Section of Endocrinology and Nutrition, Cabue\u00f1es University Hospital, 33394 Gij\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4592-3813","authenticated-orcid":false,"given":"Paula","family":"Jim\u00e9nez-Fonseca","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"Department of Medical Oncology, Central University Hospital of Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0420-2315","authenticated-orcid":false,"given":"Ignacio","family":"D\u00edaz","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of Oviedo, 33203 Gij\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-472X","authenticated-orcid":false,"given":"Jose Mar\u00eda","family":"Enguita","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, University of Oviedo, 33203 Gij\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Astudillo","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enol","family":"\u00c1lvarez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Institute of Oncology of the Principality of Asturias, University of Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9046-1171","authenticated-orcid":false,"given":"Luisa Mar\u00eda","family":"Sierra","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"Department of Functional Biology, University of Oviedo, 33006 Oviedo, Spain"},{"name":"Institute of Oncology of the Principality of Asturias, University of Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1112-1583","authenticated-orcid":false,"given":"Mar\u00eda-Dolores","family":"Chiara","sequence":"additional","affiliation":[{"name":"Institute of Sanitary Research of the Principality of Asturias, 33011 Oviedo, Spain"},{"name":"CIBERONC (Network of Biomedical Research in Cancer), 28029 Madrid, Spain"},{"name":"Institute of Oncology of the Principality of Asturias, University of Oviedo, 33006 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.tcb.2018.06.008","article-title":"The Different Routes to Metastasis via Hypoxia-Regulated Programs","volume":"28","author":"Nobre","year":"2018","journal-title":"Trends Cell 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