{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T06:15:32Z","timestamp":1762064132913,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,20]],"date-time":"2022-08-20T00:00:00Z","timestamp":1660953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Croatian Scientific Foundation","doi-asserted-by":"publisher","award":["IP-06-2016-2575"],"award-info":[{"award-number":["IP-06-2016-2575"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The expression pattern of the markers p19, Ki-67, MSX1, MSX2, PDL1, pRB, and CYCLINA2 was quantitatively and semiquantitatively analyzed in histologic sections of the developing and postnatal human eye at week 8, in retinoblastoma, and in various uveal melanomas post hoc studies by double immunofluorescence. The p19 immunoreactivity characterized retinal and\/or choroidal cells in healthy and tumor tissues: expression was lower in the postnatal retina than in the developing retina and retinoblastoma, whereas it was high in epithelioid melanomas. Ki67 expression was high in the developing eye, retinoblastoma, and choroidal melanomas. MSX1 and MSX2 expression was similar in the developing eye and retinoblastoma, whereas it was absent in the postnatal eye. Their different expression was evident between epithelioid and myxoid melanomas. Similarly, PDL1 was absent in epithelioid melanomas, whereas it was highly expressed in developing and tumor tissues. Expression of pRB and CYCA2 was characteristic of developing and tumorous eye samples but not of the healthy postnatal eye. The observed expression differences of the analyzed markers correlate with the origin and stage of cell differentiation of the tissue samples. The fine balance of expression could play a role in both human eye development and ocular tumorigenesis. Therefore, understanding their relationship and interplay could open new avenues for potential therapeutic interventions and a better understanding of the mechanisms underlying the developmental plasticity of the eye and the development of neoplasms.<\/jats:p>","DOI":"10.3390\/ijms23169421","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T22:23:13Z","timestamp":1661120593000},"page":"9421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expression of Cell Cycle Markers and Proliferation Factors during Human Eye Embryogenesis and Tumorigenesis"],"prefix":"10.3390","volume":"23","author":[{"given":"Josipa","family":"Marin Lovri\u0107","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8943-4109","authenticated-orcid":false,"given":"Natalija","family":"Filipovi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ljubo","family":"Znaor","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, 21000 Split, Croatia"},{"name":"Department of Ophthalmology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anita","family":"Ran\u010di\u0107","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1997-852X","authenticated-orcid":false,"given":"Jo\u0161ko","family":"Petri\u010devi\u0107","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nenad","family":"Kunac","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Hospital of Split, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Violeta","family":"\u0160olji\u0107","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"},{"name":"Faculty of Health Studies, University of Mostar, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mirna","family":"Saraga-Babi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2182-2890","authenticated-orcid":false,"given":"Katarina","family":"Vukojevi\u0107","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, University of Split School of Medicine, \u0160oltanska 2, 21000 Split, Croatia"},{"name":"Department of Histology and Embryology, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"},{"name":"Department of Anatomy, University of Mostar School of Medicine, 88000 Mostar, Bosnia and Herzegovina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s10735-008-9171-4","article-title":"Developmental patterns of caspase-3, bax and bcl-2 proteins expression in the human spinal ganglia","volume":"39","author":"Vukojevic","year":"2008","journal-title":"J. Mol. Histol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"\u017du\u017eul, M., Lozi\u0107, M., Filipovi\u0107, N., \u010canovi\u0107, S., Didovi\u0107 Pavi\u010di\u0107, A., Petri\u010devi\u0107, J., Kunac, N., \u0160olji\u0107, V., Saraga-Babi\u0107, M., and Konjevoda, S. (2022). The Expression of Connexin 37, 40, 43, 45 and Pannexin 1 in the Early Human Retina and Choroid Development and Tumorigenesis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23115918"},{"key":"ref_3","first-page":"33","article-title":"Activation of PI3K\/AKT is involved in TINAG-mediated promotion of proliferation, invasion and migration of hepatocellular carcinoma","volume":"23","author":"Zhang","year":"2018","journal-title":"Cancer Biomark. Sect. A Dis. Markers"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1080\/02713683.2019.1623898","article-title":"Associations among Socioeconomic Factors, Lag Time, and High-Risk Histopathologic Features in Eyes Primarily Enucleated for Retinoblastoma","volume":"44","author":"Xiao","year":"2019","journal-title":"Curr. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/eye.2016.275","article-title":"Uveal melanoma: Relatively rare but deadly cancer","volume":"31","author":"Kaliki","year":"2017","journal-title":"Eye (Lond)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.sjopt.2013.06.002","article-title":"Ocular tumors: Triumphs, challenges and controversies","volume":"27","author":"Eagle","year":"2013","journal-title":"Saudi J. Ophthalmol. Off. J. Saudi Ophthalmol. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/eye.2012.237","article-title":"The pathology of ocular cancer","volume":"27","author":"Eagle","year":"2013","journal-title":"Eye"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1080\/15476278.2017.1358337","article-title":"Regulation of proliferation in developing human tooth germs by MSX homeodomain proteins and cyclin-dependent kinase inhibitor p19(INK4d)","volume":"13","author":"Kero","year":"2017","journal-title":"Organogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1101\/gad.282145.116","article-title":"RB1: A prototype tumor suppressor and an enigma","volume":"30","author":"Dyson","year":"2016","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.archoralbio.2014.05.025","article-title":"Expression of Ki-67, Oct-4, gamma-tubulin and alpha-tubulin in human tooth development","volume":"59","author":"Kero","year":"2014","journal-title":"Arch. Oral Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1939-1676.2001.tb02326.x","article-title":"Cellular proliferation in tumors: A review of methods, interpretation, and clinical applications","volume":"15","author":"Madewell","year":"2001","journal-title":"J. Vet. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/15216540701488358","article-title":"INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions","volume":"59","author":"Canepa","year":"2007","journal-title":"IUBMB Life"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.devcel.2016.11.020","article-title":"Msx1-Positive Progenitors in the Retinal Ciliary Margin Give Rise to Both Neural and Non-neural Progenies in Mammals","volume":"40","author":"Belanger","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.bbrc.2010.04.058","article-title":"Msx2 alters the timing of retinal ganglion cells fate commitment and differentiation","volume":"395","author":"Jiang","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/bjc.2011.249","article-title":"Functional and prognostic relevance of the homeobox protein MSX2 in malignant melanoma","volume":"105","author":"Gremel","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.exer.2007.09.007","article-title":"Functional expression of B7H1 on retinal pigment epithelial cells","volume":"86","author":"Usui","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1515\/bmc-2012-0027","article-title":"Cyclin A2: A genuine cell cycle regulator?","volume":"3","author":"Bendris","year":"2012","journal-title":"Biomol. Concepts"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Verdugo-Sivianes, E.M., and Carnero, A. (2021). Role of the Holoenzyme PP1-SPN in the Dephosphorylation of the RB Family of Tumor Suppressors During Cell Cycle. Cancers, 13.","DOI":"10.3390\/cancers13092226"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1007\/s00417-015-3128-6","article-title":"Interplay of proliferation and differentiation factors is revealed in the early human eye development","volume":"253","author":"Matas","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00429-004-0410-5","article-title":"Cell proliferation during the early stages of human eye development","volume":"208","author":"Bozanic","year":"2004","journal-title":"Anat. Embryol."},{"key":"ref_21","first-page":"91","article-title":"Proliferation and differentiation of glial and neuronal progenitors in the development of human spinal ganglia","volume":"78","author":"Vukojevic","year":"2009","journal-title":"Differ. Res. Biol. Divers."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.4103\/0301-4738.154367","article-title":"Uveal melanoma: Estimating prognosis","volume":"63","author":"Kaliki","year":"2015","journal-title":"Indian J. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Tang, Y., Durand, S., Dalle, S., and Caramel, J. (2020). EMT-Inducing Transcription Factors, Drivers of Melanoma Phenotype Switching, and Resistance to Treatment. Cancers, 12.","DOI":"10.3390\/cancers12082154"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1167\/iovs.62.2.6","article-title":"Retinoblastoma Is Characterized by a Cold, CD8+ Cell Poor, PD-L1- Microenvironment, Which Turns Into Hot, CD8+ Cell Rich, PD-L1+ After Chemotherapy","volume":"62","author":"Miracco","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kim, D.H., Xing, T., Yang, Z., Dudek, R., Lu, Q., and Chen, Y.H. (2017). Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview. J. Clin. Med., 7.","DOI":"10.3390\/jcm7010001"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Guzman, F., Fazeli, Y., Khuu, M., Salcido, K., Singh, S., and Benavente, C.A. (2020). Retinoblastoma Tumor Suppressor Protein Roles in Epigenetic Regulation. Cancers, 12.","DOI":"10.3390\/cancers12102807"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ding, L., Cao, J., Lin, W., Chen, H., Xiong, X., Ao, H., Yu, M., Lin, J., and Cui, Q. (2020). The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061960"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1097\/01.cmr.0000232290.61042.ee","article-title":"Cyclin-dependent kinase 2 expression in human melanomas and benign melanocytic skin lesions","volume":"16","author":"Kuzbicki","year":"2006","journal-title":"Melanoma Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e19","DOI":"10.1017\/S1462399408000744","article-title":"P21 and p27: Roles in carcinogenesis and drug resistance","volume":"10","author":"Abukhdeir","year":"2008","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.3892\/ijo.2015.3179","article-title":"OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways","volume":"47","author":"Li","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.3892\/ol.2015.2857","article-title":"Enhanced SOX2 expression in retinoblastoma tissues and peripheral blood is associated with the clinicopathological characteristics of the disease","volume":"9","author":"Tong","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4516","DOI":"10.1038\/onc.2017.55","article-title":"Sox2 is dispensable for primary melanoma and metastasis formation","volume":"36","author":"Schaefer","year":"2017","journal-title":"Oncogene"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.mod.2016.11.002","article-title":"Evolution of the Rax family of developmental transcription factors in vertebrates","volume":"144 Pt B","author":"Orquera","year":"2017","journal-title":"Mech. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5387","DOI":"10.1074\/jbc.M310383200","article-title":"Expression of cyclin E renders cyclin D-CDK4 dispensable for inactivation of the retinoblastoma tumor suppressor protein, activation of E2F, and G1-S phase progression","volume":"279","author":"Keenan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151679","DOI":"10.1016\/j.acthis.2021.151679","article-title":"GREB1L, CRELD2 and ITGA10 expression in the human developmental and postnatal kidneys: An immunohistochemical study","volume":"123","author":"Lasic","year":"2021","journal-title":"Acta Histochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"521","DOI":"10.3325\/cmj.2019.60.521","article-title":"Expression and localization of DAB1 and Reelin during normal human kidney development","volume":"60","author":"Racetin","year":"2019","journal-title":"Croat. Med. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.acthis.2019.04.011","article-title":"Immunohistochemical expression pattern of RIP5, FGFR1, FGFR2 and HIP2 in the normal human kidney development","volume":"121","author":"Racetin","year":"2019","journal-title":"Acta Histochem."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Caric, D., Zekic Tomas, S., Filipovic, N., Soljic, V., Benzon, B., Glumac, S., Rakovac, I., and Vukojevic, K. (2021). Expression Pattern of iNOS, BCL-2 and MMP-9 in the Hip Synovium Tissue of Patients with Osteoarthritis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031489"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Jelicic, I., Vukojevic, K., Racetin, A., Caric, D., Glavina Durdov, M., Saraga-Babic, M., and Filipovic, N. (2022). Expression of Pannexin 1 in the Human Kidney during Embryonal, Early Fetal and Postnatal Development and Its Prognostic Significance in Diabetic Nephropathy. Biomedicines, 10.","DOI":"10.3390\/biomedicines10050944"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9421\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:13:00Z","timestamp":1760141580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/9421"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,20]]},"references-count":39,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23169421"],"URL":"https:\/\/doi.org\/10.3390\/ijms23169421","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,8,20]]}}}