{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T01:51:49Z","timestamp":1775526709381,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T00:00:00Z","timestamp":1563321600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: The odontogenic keratocyst (OKC) is an odontogenic cyst that shows aggressive and intriguing biological behavior. It is suggested that a hypoxic environment occurs in OKC, which led us to investigate the immunoexpression and location of hypoxia-inducible factor 1-alpha (HIF-1\u03b1) and other hypoxia-related proteins. Methods: Twenty cases of OKC were evaluated for the expression of Notch homolog 1 (NOTCH1), HIF-1\u03b1, disintegrin and metalloproteinase domain-containing protein 12 (ADAM-12), and heparin-binding epidermal growth factor-like growth factor (HBEGF) by immunohistochemistry and compared to eight control cases of calcifying odontogenic cystic (COC), orthokeratinized odontogenic cyst (OOC), and normal oral mucosa (OM) in basal and parabasal layers. Results: In OKC, all the proteins tested were expressed significantly higher in both basal (except for NOTCH1 and HBEGF in OOC) and suprabasal epithelial layers compared to controls. Looking at the epithelial layers within OKC, we observed an increased NOTCH1 and HIF-1\u03b1 expression in parabasal layers. Conclusions: These results suggest that hypoxia occurs more intensively in OKC compared to COC, OM, and OOC. Hypoxia appeared to be stronger in parabasal layers as observed by higher HIF-1\u03b1 expression in upper cells. Overexpression of NOTCH1, ADAM-12, and HBEGF in OKC was observed, which suggests that microenvironmental hypoxia could potentially regulate the expression of hypoxia-related proteins, and consequently, its clinical and biological behavior.<\/jats:p>","DOI":"10.3390\/cells8070731","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T11:25:12Z","timestamp":1563362712000},"page":"731","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["HIF-1\u03b1 is Overexpressed in Odontogenic Keratocyst Suggesting Activation of HIF-1\u03b1 and NOTCH1 Signaling Pathways"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7852-4697","authenticated-orcid":false,"given":"Natacha Malu","family":"Miranda da Costa","sequence":"first","affiliation":[{"name":"Department of Buco-Maxillofacial Surgery and Traumatology and Periodontology, School of Dentistry of Ribeir\u00e3o Preto, University of S\u00e3o Paulo, Av. do Caf\u00e9-Subsetor Oeste-11 (N-11), 14040-904 Ribeir\u00e3o Preto, SP, Brazil"},{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caio Tadashi","family":"Saab Abe","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geovanni Pereira","family":"Mitre","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-4007","authenticated-orcid":false,"given":"Ricardo Alves","family":"Mesquita","sequence":"additional","affiliation":[{"name":"Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais, R. Prof. Moacir Gomes de Freitas, 688-Pampulha, 31270-901 Belo Horizonte, MG, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Sueli da","family":"Silva Kataoka","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8124-2156","authenticated-orcid":false,"given":"Andr\u00e9 Luis","family":"Ribeiro Ribeiro","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruy Gastaldoni","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology Institute of Biomedical Sciences, University of S\u00e3o Paulo, Av. Prof. Lineu Prestes, 1374-Butant\u00e3, 05508-900 S\u00e3o Paulo, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9rgio de Melo","family":"Alves-J\u00fanior","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4691-5973","authenticated-orcid":false,"given":"Andrew Mark","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Microbial Diseases, Eastman Dental Institute, University College London, 256 Grays Inn Rd, London WC1X 8LD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jo\u00e3o de Jesus Viana","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Cell Culture Laboratory, School of Dentistry, Federal University of Par\u00e1 (UFPA), Cidade Universit\u00e1ria Prof. Jos\u00e9 da Silveira Neto-R. Augusto Corr\u00eaa, 1-Guam\u00e1, 66075-110 Bel\u00e9m, PA, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,17]]},"reference":[{"key":"ref_1","unstructured":"El-Naggar, A.K., Chan, J.K.C., Grandis, J.R., Takata, T., and Slootweg, P.J. (2017). WHO Classification of Head and Neck Tumours, IARC Press. [4th ed.]."},{"key":"ref_2","unstructured":"Barnes, L., Eveson, J.W., Reichart, P., and Sidransky, D. (2005). World Health Organization Classification of Tumours Pathology and Genetics Head and Neck Tumours, IARC Press."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/S1368-8375(01)00067-7","article-title":"The aggressive nature of the odontogenic keratocyst: Is it a benign cystic neoplasm? Part 3. 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