{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:20:29Z","timestamp":1785410429505,"version":"3.56.0"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PAPIIT-UNAM","award":["202322"],"award-info":[{"award-number":["202322"]}]},{"name":"PAPIIT-UNAM","award":["21727223"],"award-info":[{"award-number":["21727223"]}]},{"name":"PAPIIT-UNAM","award":["203425"],"award-info":[{"award-number":["203425"]}]},{"name":"Secretaria de Ciencias, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","award":["862245"],"award-info":[{"award-number":["862245"]}]},{"award":["862245"],"award-info":[{"award-number":["862245"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The study investigates the impact of molecular iodine (I2) supplementation on the viability, invasiveness, and angiogenic potential of high-risk neuroblastoma (NB). In vitro assays were performed using NB cell lines SK-N-AS (non-MYCN-amplified) and SK-N-BE(2) (MYCN-amplified). The role of peroxisome proliferator-activated receptor gamma (PPAR\u03b3) was evaluated using the antagonist GW9662, gene expression (RT-qPCR), and protein levels (Western blot). In vivo, zebrafish xenografts were used to evaluate tumor size, angiogenesis, and caudal cell dissemination. I2 supplementation significantly decreased cell viability in both cell lines, independent of PPAR\u03b3 activation. In SK-N-BE(2), I2 impaired cell migration, as measured by a wound-healing assay, in apparent independence of PPAR\u03b3 activation. However, gene expression indicates that I2 acts in complex ways, including direct antioxidant effects and PPAR\u03b3-mediated effects. The significant decrease in reactive oxygen species levels (DCFDA staining) and the silencing of the long noncoding RNA myocardial infarction-associated transcript (MIAT) by I2 were directly associated with decreased MYCN and TrkB expression. In contrast, PPAR\u03b3 activation was accompanied by overexpression of FasN and TrkA and a significant decrease in Aurka, a MYCN-stabilizing protein. In zebrafish, I2-pretreated SK-N-BE(2) xenografts exhibited a clear reduction in angiogenesis (vascular density) and a decrease in invasive capacity. In conclusion, I2 supplementation decreases cell viability and attenuates invasion and angiogenesis in NB cells, highlighting its potential as an adjuvant to conventional therapy for high-risk NB.<\/jats:p>","DOI":"10.3390\/cells15131189","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:56:55Z","timestamp":1782838615000},"page":"1189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Iodine\/PPAR\u03b3 Interaction in the Invasion and Angiogenesis of Neuroblastoma Xenografts"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5865-2437","authenticated-orcid":false,"given":"Edgar R.","family":"Juvera-Avalos","sequence":"first","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Juriquilla 76230, Queretaro, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Orizaga-Osti","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Juriquilla 76230, Queretaro, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2605-4632","authenticated-orcid":false,"given":"Evangelina","family":"Delgado-Gonzalez","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Juriquilla 76230, Queretaro, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilda","family":"Lomeli","sequence":"additional","affiliation":[{"name":"Instituto de Biotecnolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Cuernavaca 62210, Morelos, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7744-8685","authenticated-orcid":false,"given":"Brenda","family":"Anguiano","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Juriquilla 76230, Queretaro, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-8304","authenticated-orcid":false,"given":"Carmen","family":"Aceves","sequence":"additional","affiliation":[{"name":"Instituto de Neurobiolog\u00eda, Universidad Nacional Aut\u00f3noma de Mexico, Juriquilla 76230, Queretaro, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/s41571-022-00643-z","article-title":"Advancing Therapy for Neuroblastoma","volume":"19","author":"Qiu","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Otte, J., Dyberg, C., Pepich, A., and Johnsen, J.I. (2021). MYCN Function in Neuroblastoma Development. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.624079"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1007\/s00595-019-01790-0","article-title":"The Roles Played by the MYCN, Trk, and ALK Genes in Neuroblastoma and Neural Development","volume":"49","author":"Higashi","year":"2019","journal-title":"Surg. Today"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1158\/2159-8290.CD-17-0273","article-title":"The Expanding World of N-MYC\u2013Driven Tumors","volume":"8","author":"Rickman","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/0092-8674(83)90169-1","article-title":"Transposition and Amplification of Oncogene-Related Sequences in Human Neuroblastomas","volume":"35","author":"Kohl","year":"1983","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1101\/gad.1021202","article-title":"N-Myc Is Essential during Neurogenesis for the Rapid Expansion of Progenitor Cell Populations and the Inhibition of Neuronal Differentiation","volume":"16","author":"Knoepfler","year":"2002","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Bhavsar, S.P. (2023). Metastasis in Neuroblastoma: The MYCN Question. Front Oncol., 13.","DOI":"10.3389\/fonc.2023.1196861"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"a014415","DOI":"10.1101\/cshperspect.a014415","article-title":"Neuroblastoma and MYCN","volume":"3","author":"Huang","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1016\/S0140-6736(07)60983-0","article-title":"Neuroblastoma","volume":"369","author":"Maris","year":"2007","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1056\/NEJM199303253281205","article-title":"Association between High Levels of Expression of the TRK Gene and Favorable Outcome in Human Neuroblastoma","volume":"328","author":"Nakagawara","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nakatani, K., Kogashi, H., Miyamoto, T., Setoguchi, T., Sakuma, T., Kugou, K., Hasegawa, Y., Yamamoto, T., Hippo, Y., and Suenaga, Y. (2024). Inhibition of OCT4 Binding at the MYCN Locus Induces Neuroblastoma Cell Death Accompanied by Downregulation of Transcripts with High-Open Reading Frame Dominance. Front Oncol., 14.","DOI":"10.3389\/fonc.2024.1237378"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.ijbiomac.2019.03.005","article-title":"RNA Sequencing Reveals a Key Role for the Long Non-Coding RNA MIAT in Regulating Neuroblastoma and Glioblastoma Cell Fate","volume":"130","author":"Bountali","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Feriancikova, B., Feglarova, T., Krskova, L., Eckschlager, T., Vicha, A., and Hrabeta, J. (2021). MIAT Is an Upstream Regulator of NMYC and the Disruption of the MIAT\/NMYC Axis Induces Cell Death in NMYC Amplified Neuroblastoma Cell Lines. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073393"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zohar, K., Giladi, E., Eliyahu, T., and Linial, M. (2022). Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells. Non-Coding RNA, 8.","DOI":"10.3390\/ncrna8060072"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3244","DOI":"10.1158\/1078-0432.CCR-08-1815","article-title":"Trk Receptor Expression and Inhibition in Neuroblastomas","volume":"15","author":"Brodeur","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e3038164","DOI":"10.1155\/2016\/3038164","article-title":"PPAR Gamma in Neuroblastoma: The Translational Perspectives of Hypoglycemic Drugs","volume":"2016","author":"Vella","year":"2016","journal-title":"PPAR Res."},{"key":"ref_17","first-page":"98","article-title":"Novel Expression and Function of Peroxisome Proliferator-Activated Receptor Gamma (PPAR\u03b3) in Human Neuroblastoma Cells1","volume":"7","author":"Han","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.metabol.2017.09.013","article-title":"Adverse Glycaemic Effects of Cancer Therapy: Indications for a Rational Approach to Cancer Patients with Diabetes","volume":"78","author":"Gallo","year":"2018","journal-title":"Metabolism"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1530\/ERC-20-0354","article-title":"Molecular Iodine Synergized and Sensitized Neuroblastoma Cells to the Antineoplastic Effect of ATRA","volume":"27","author":"Mendieta","year":"2020","journal-title":"Endocr.-Relat. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"\u00c1lvarez-Le\u00f3n, W., Mendieta, I., Delgado-Gonz\u00e1lez, E., Anguiano, B., and Aceves, C. (2021). Molecular Iodine\/Cyclophosphamide Synergism on Chemoresistant Neuroblastoma Models. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168936"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Aceves, C., Mendieta, I., Anguiano, B., and Delgado-Gonz\u00e1lez, E. (2021). Molecular Iodine Has Extrathyroidal Effects as an Antioxidant, Differentiator, and Immunomodulator. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031228"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"19762","DOI":"10.1074\/jbc.M600746200","article-title":"Molecular Iodine Induces Caspase-Independent Apoptosis in Human Breast Carcinoma Cells Involving the Mitochondria-Mediated Pathway","volume":"281","author":"Shrivastava","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.freeradbiomed.2017.01.011","article-title":"A Novel Role of Topical Iodine in Skin: Activation of the Nrf2 Pathway","volume":"104","author":"Soroka","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Cuenca-Mic\u00f3, O., Delgado-Gonz\u00e1lez, E., Anguiano, B., Vaca-Paniagua, F., Medina-Rivera, A., Rodr\u00edguez-Dorantes, M., and Aceves, C. (2021). Effects of Molecular Iodine\/Chemotherapy in the Immune Component of Breast Cancer Tumoral Microenvironment. Biomolecules, 11.","DOI":"10.20944\/preprints202109.0170.v1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1476-4598-8-33","article-title":"Antineoplastic Effect of Iodine in Mammary Cancer: Participation of 6-Iodolactone (6-IL) and Peroxisome Proliferator-Activated Receptors (PPAR)","volume":"8","author":"Aceves","year":"2009","journal-title":"Mol. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/0161-4630(78)90074-5","article-title":"Arachidonic Acid Distribution in Lipids of Mammary Glands and Dmba-Induced Tumors of Rats","volume":"1","author":"Rillema","year":"1978","journal-title":"Prostaglandins Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-3-319-30654-4_5","article-title":"Cancer and Zebrafish: Mechanisms, Techniques, and Models: Chemical Genetics","volume":"916","author":"Dang","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_28","first-page":"1","article-title":"Production and Optimization of a Vasostatin-30 and Vasoinhibin Fusion Protein That Inhibits Tumor Angiogenesis and Dissemination of Breast Cancer Cells in a Zebrafish Model","volume":"119","author":"Gonzalez","year":"2022","journal-title":"Process Biochem."},{"key":"ref_29","first-page":"345","article-title":"The Cellular Response to PPAR\u03b3 Ligands Is Related to the Phenotype of Neuroblastoma Cell Lines","volume":"14","author":"Servidei","year":"2004","journal-title":"Oncol. Res. Featur. Preclin. Clin. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1200\/JCO.2008.17.9184","article-title":"Significance of MYCN Amplification in International Neuroblastoma Staging System Stage 1 and 2 Neuroblastoma: A Report from the International Neuroblastoma Risk Group Database","volume":"27","author":"Bagatell","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_31","first-page":"122","article-title":"The uptake of potassium iodide and its effect as an antioxidant in isolated rabbit eyes","volume":"191","author":"Elstner","year":"1985","journal-title":"Ophthalmologica"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1002\/(SICI)1099-0844(200006)18:2<143::AID-CBF857>3.0.CO;2-#","article-title":"Effect of Iodide on Total Antioxidant Status of Human Serum","volume":"18","author":"Winkler","year":"2000","journal-title":"Cell Biochem Funct."},{"key":"ref_33","first-page":"15","article-title":"Iodide, Antioxidant Function and Omega-6 and Omega-3 Fatty Acids","volume":"2","author":"Cocchi","year":"2000","journal-title":"Prog. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.ccell.2020.06.001","article-title":"Oxidative Stress in Cancer","volume":"38","author":"Hayes","year":"2020","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41416-019-0650-z","article-title":"Reprogramming of Fatty Acid Metabolism in Cancer","volume":"122","author":"Koundouros","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.phrs.2018.02.022","article-title":"Lipid Pathway Deregulation in Advanced Prostate Cancer","volume":"131","author":"Galbraith","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"104655","DOI":"10.1016\/j.isci.2022.104655","article-title":"TTF1 Suppresses Neuroblastoma Growth and Induces Neuroblastoma Differentiation by Targeting TrkA and the miR-204\/TrkB Axis","volume":"25","author":"Yang","year":"2022","journal-title":"iScience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1158\/1535-7163.MCT-09-0036","article-title":"Identification and Preclinical Characterization of AZ-23, a Novel, Selective, and Orally Bioavailable Inhibitor of the Trk Kinase Pathway","volume":"8","author":"Thress","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1200\/JCO.2008.16.6876","article-title":"The International Neuroblastoma Risk Group (INRG) Staging System: An INRG Task Force Report","volume":"27","author":"Monclair","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9604","DOI":"10.1074\/jbc.M409447200","article-title":"Peroxisome Proliferator-Activated Receptor \u03b3 Is a Novel Target of the Nerve Growth Factor Signaling Pathway in PC12 Cells","volume":"280","author":"Fuenzalida","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Chu, J. (2024). Validation of the Biological Function and Prognostic Significance of AURKA in Neuroblastoma. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0313939"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ccr.2008.12.005","article-title":"Stabilization of N-Myc Is a Critical Function of Aurora A in Human Neuroblastoma","volume":"15","author":"Otto","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"21416","DOI":"10.1021\/acsomega.4c01752","article-title":"Preclinical Evaluation of JAB-2485, a Potent AURKA Inhibitor with High Selectivity and Favorable Pharmacokinetic Properties","volume":"9","author":"Yang","year":"2024","journal-title":"ACS Omega"},{"key":"ref_44","first-page":"3998","article-title":"Differentiation of Human Neuroblastoma by Phenylacetate Is Mediated by Peroxisome Proliferator-Activated Receptor Gamma","volume":"61","author":"Han","year":"2001","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Loh, C.-Y., Chai, J.Y., Tang, T.F., Wong, W.F., Sethi, G., Shanmugam, M.K., Chong, P.P., and Looi, C.Y. (2019). The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells, 8.","DOI":"10.3390\/cells8101118"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2300037","DOI":"10.1002\/adbi.202300037","article-title":"Partial Activation of PPAR-\u03b3 by Synthesized Quercetin Derivatives Modulates TGF-\u03921-Induced EMT in Lung Cancer Cells","volume":"7","author":"Ballav","year":"2023","journal-title":"Adv. Biol."},{"key":"ref_47","first-page":"1900","article-title":"High-Level Expression of Angiogenic Factors Is Associated with Advanced Tumor Stage in Human Neuroblastomas","volume":"6","author":"Eggert","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Cabezas-S\u00e1inz, P., Pensado-L\u00f3pez, A., S\u00e1inz, B., and S\u00e1nchez, L. (2020). Modeling Cancer Using Zebrafish Xenografts: Drawbacks for Mimicking the Human Microenvironment. Cells, 9.","DOI":"10.3390\/cells9091978"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1158\/0008-5472.CAN-06-4268","article-title":"Mammalian Tumor Xenografts Induce Neovascularization in Zebrafish Embryos","volume":"67","author":"Nicoli","year":"2007","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.1158\/0008-5472.CAN-13-3396","article-title":"Genome-Wide Profiling of AP-1\u2013Regulated Transcription Provides Insights into the Invasiveness of Triple-Negative Breast Cancer","volume":"74","author":"Zhao","year":"2014","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Miller, A., Schr\u00f6der, K.L., Braun, K.E., Steindorf, C., Ottermanns, R., Ro\u00df-Nickoll, M., Hollert, H., and Backhaus, T. (2025). Temperature-Dependence of Early Development of Zebrafish and the Consequences for Laboratory Use and Animal Welfare. PLoS ONE, 20.","DOI":"10.1101\/2025.02.13.638062"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.1038\/nprot.2007.412","article-title":"The Zebrafish\/Tumor Xenograft Angiogenesis Assay","volume":"2","author":"Nicoli","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/13\/1189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:14:34Z","timestamp":1782839674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/13\/1189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":52,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15131189"],"URL":"https:\/\/doi.org\/10.3390\/cells15131189","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}