{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:57:28Z","timestamp":1781639848911,"version":"3.54.5"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Faculdade Israelita De Ci\u00eancias Da Sa\u00fade Albert Einstein"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Endocrine"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Radioiodine (RAI) refractoriness and tumor dedifferentiation are major contributors to poor outcomes in metastatic papillary thyroid carcinoma (PTC). microRNAs (miRNAs) are promising biomarkers to identify these aggressive phenotypes. This study aimed to characterize miRNAs expression profiles associated with RAI refractoriness and dedifferentiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      From a cohort of 108 metastatic PTC patients, 24 cases with available formalin-fixed paraffin-embedded tissue were selected for molecular analysis, including 17 patients who died from disease progression and 7 long-term survivors with stable disease. Total RNA was extracted and analyzed by qPCR. miRNAs with differential expression (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.10) in univariate analysis were included in multivariate linear regression models. Diagnostic performance was assessed using ROC curve analysis and hierarchical clustering.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The cohort had a mean age of 55.2 years and was predominantly male (66.7%). RAI-refractory disease was present in 63.2% of evaluable cases, and dedifferentiation in 33.3%. In multivariate analysis, lower expression of miR-200c-3p was independently associated with RAI refractoriness (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.005). For tumor dedifferentiation, higher expression of let-7i-5p (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001) and miR-19b-3p (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001), and lower expression of miR-31-5p (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.004) and let-7e-5p (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.036), were independently associated. ROC curve analysis demonstrated high diagnostic accuracy for miR-200c-3p (AUC\u2009=\u20090.929) and let-7i-5p (AUC\u2009=\u20090.958) for, respectively, RAI refractoriness and tumor dedifferentiation. Heatmap analysis revealed clear segregation of phenotypic groups based on miRNA expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Distinct miRNAs signatures are associated with RAI refractoriness and tumor dedifferentiation in metastatic PTC. These findings support their potential as prognostic biomarkers and may guide future therapeutic stratification.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12020-025-04510-6","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T14:11:35Z","timestamp":1773065495000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MicroRNA signatures associated with radioiodine refractoriness and tumor dedifferentiation in metastatic papillary thyroid carcinoma"],"prefix":"10.1007","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7814-757X","authenticated-orcid":false,"given":"Ana Kober","family":"Leite","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6397-6754","authenticated-orcid":false,"given":"Kelly Cristina","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-2622","authenticated-orcid":false,"given":"Th\u00e9r\u00e8se Rachell","family":"Theodoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0361-7781","authenticated-orcid":false,"given":"F\u00e1tima Solange","family":"Pasini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ven\u00e2ncio Avancini Ferreira","family":"Alves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5865-9308","authenticated-orcid":false,"given":"Luiz Paulo","family":"Kowalski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4001-1663","authenticated-orcid":false,"given":"Maria Aparecida Silva","family":"Pinhal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7281-4044","authenticated-orcid":false,"given":"Gilberto Mendes Junior","family":"Menderico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-4459","authenticated-orcid":false,"given":"Edna Teruko","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-8208","authenticated-orcid":false,"given":"Leandro Luongo","family":"Matos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"key":"4510_CR1","doi-asserted-by":"crossref","unstructured":"1. Cernea CR, Matos LL, Eug\u00eanio C, Ferreira GM, Cerqueira YS, Leite AKN, et al. Active Surveillance of Thyroid Microcarcinomas: a Critical View. Curr Oncol Rep. 2022;24(1):69\u201376.","DOI":"10.1007\/s11912-021-01177-w"},{"key":"4510_CR2","doi-asserted-by":"crossref","unstructured":"2. Benbassat CA, Mechlis-Frish S, Hirsch D. Clinicopathological characteristics and long-term outcome in patients with distant metastases from differentiated thyroid cancer. World J Surg. 2006;30(6):1088-95.","DOI":"10.1007\/s00268-005-0472-4"},{"key":"4510_CR3","doi-asserted-by":"crossref","unstructured":"3. Shaha AR, Shah JP, Loree TR. Differentiated thyroid cancer presenting initially with distant metastasis. Am J Surg. 1997;174(5):474-6.","DOI":"10.1016\/S0002-9610(97)00158-X"},{"key":"4510_CR4","doi-asserted-by":"crossref","unstructured":"4. Sugitani I, Fujimoto Y, Yamamoto N. Papillary thyroid carcinoma with distant metastases: survival predictors and the importance of local control. Surgery. 2008;143(1):35\u201342.","DOI":"10.1016\/j.surg.2007.06.011"},{"key":"4510_CR5","doi-asserted-by":"crossref","unstructured":"5. Chan WWL, Chan S, Kwong DLW. Radioiodine Refractory Differentiated Thyroid Cancer. Methods Mol Biol. 2022;2534:243\u2009\u2212\u200957.","DOI":"10.1007\/978-1-0716-2505-7_17"},{"key":"4510_CR6","doi-asserted-by":"crossref","unstructured":"6. Fallahi P, Mazzi V, Vita R, Ferrari SM, Materazzi G, Galleri D, et al. New therapies for dedifferentiated papillary thyroid cancer. Int J Mol Sci. 2015;16(3):6153-82.","DOI":"10.3390\/ijms16036153"},{"key":"4510_CR7","doi-asserted-by":"crossref","unstructured":"7. Cai Y, Yu X, Hu S, Yu J. A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics. 2009;7(4):147\u2009\u2212\u200954.","DOI":"10.1016\/S1672-0229(08)60044-3"},{"key":"4510_CR8","doi-asserted-by":"crossref","unstructured":"8. Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234(5):5451-65.","DOI":"10.1002\/jcp.27486"},{"key":"4510_CR9","doi-asserted-by":"crossref","unstructured":"9. Yip L, Kelly L, Shuai Y, Armstrong MJ, Nikiforov YE, Carty SE, et al. MicroRNA signature distinguishes the degree of aggressiveness of papillary thyroid carcinoma. Ann Surg Oncol. 2011;18(7):2035-41.","DOI":"10.1245\/s10434-011-1733-0"},{"key":"4510_CR10","doi-asserted-by":"crossref","unstructured":"10. Fuziwara CS, Kimura ET. MicroRNA Deregulation in Anaplastic Thyroid Cancer Biology. Int J Endocrinol. 2014;2014:743450.","DOI":"10.1155\/2014\/743450"},{"key":"4510_CR11","doi-asserted-by":"crossref","unstructured":"11. Leite AK, Saito KC, Theodoro TR, Pasini FS, Camilo LP, Rossetti CA, et al. Profile of MicroRNAs Associated with Death Due to Disease Progression in Metastatic Papillary Thyroid Carcinoma Patients. Cancers (Basel). 2023;15(3).","DOI":"10.3390\/cancers15030869"},{"key":"4510_CR12","doi-asserted-by":"crossref","unstructured":"12. Pecce V, Sponziello M, Verrienti A, Grani G, Abballe L, Bini S, et al. The role of miR-139-5p in radioiodine-resistant thyroid cancer. J Endocrinol Invest. 2023;46(10):2079-93.","DOI":"10.1007\/s40618-023-02059-7"},{"key":"4510_CR13","doi-asserted-by":"crossref","unstructured":"13. Colombo C, Minna E, Gargiuli C, Muzza M, Dugo M, De Cecco L, et al. The molecular and gene\/miRNA expression profiles of radioiodine resistant papillary thyroid cancer. J Exp Clin Cancer Res. 2020;39(1):245.","DOI":"10.1186\/s13046-020-01757-x"},{"key":"4510_CR14","doi-asserted-by":"crossref","unstructured":"14. Zhang P, Guan L, Sun W, Zhang Y, Du Y, Yuan S, et al. Targeting miR-31 represses tumourigenesis and dedifferentiation of BRAF(V600E)-associated thyroid carcinoma. Clin Transl Med. 2024;14(5):e1694.","DOI":"10.1002\/ctm2.1694"},{"key":"4510_CR15","unstructured":"15. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al. AJCC cancer staging manual. 8th ed. Chicago: Springer; 2017."},{"key":"4510_CR16","doi-asserted-by":"crossref","unstructured":"16. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133.","DOI":"10.1089\/thy.2015.0020"},{"key":"4510_CR17","doi-asserted-by":"crossref","unstructured":"17. Matos LL, Menderico Junior GM, Theodoro TR, Pasini FS, Ishikawa MM, Ribeiro AAB, et al. Cancer-associated fibroblast regulation by microRNAs promotes invasion of oral squamous cell carcinoma. Oral Oncol. 2020;110:104909.","DOI":"10.1016\/j.oraloncology.2020.104909"},{"key":"4510_CR18","doi-asserted-by":"crossref","unstructured":"18. Ulitsky I, Maron-Katz A, Shavit S, Sagir D, Linhart C, Elkon R, et al. Expander: from expression microarrays to networks and functions. Nat Protoc. 2010;5(2):303\u2009\u2212\u200922.","DOI":"10.1038\/nprot.2009.230"},{"key":"4510_CR19","doi-asserted-by":"crossref","unstructured":"19. Andersen CL, Jensen JL, \u00d8rntoft TF. Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004;64(15):5245-50.","DOI":"10.1158\/0008-5472.CAN-04-0496"},{"key":"4510_CR20","doi-asserted-by":"crossref","unstructured":"20. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3(7):RESEARCH0034.","DOI":"10.1186\/gb-2002-3-7-research0034"},{"key":"4510_CR21","doi-asserted-by":"crossref","unstructured":"21. Qiu ZL, Shen CT, Song HJ, Wei WJ, Luo QY. Differential expression profiling of circulation microRNAs in PTC patients with non-131I and 131I-avid lungs metastases: a pilot study. Nucl Med Biol. 2015;42(5):499\u2013504.","DOI":"10.1016\/j.nucmedbio.2015.01.009"},{"key":"4510_CR22","doi-asserted-by":"crossref","unstructured":"22. Feng YL, Ke T, Wang GL, Qi HY, Xiao Y. MicroRNA-200c-3p Negatively Regulates ATP2A2 and Promotes the Progression of Papillary Thyroid Carcinoma. Biochem Genet. 2022;60(5):1676-94.","DOI":"10.1007\/s10528-022-10184-w"},{"key":"4510_CR23","doi-asserted-by":"crossref","unstructured":"23. Leite AKN, Cavalheiro BG, Kulcsar MA, Hoff AO, Brand\u00e3o LG, Cernea CR, et al. Deaths related to differentiated thyroid cancer: a rare but real event. Arch Endocrinol Metab. 2017;61(3):222-7.","DOI":"10.1590\/2359-3997000000261"},{"key":"4510_CR24","doi-asserted-by":"crossref","unstructured":"24. Leite AK, Kulcsar MA, de Godoi Cavalheiro B, de Mello ES, Alves VA, Cernea CR, et al. Death Related to Pulmonary Metastasis in Patients with Differentiated Thyroid Cancer. Endocr Pract. 2017;23(1):72\u2009\u2212\u20098.","DOI":"10.4158\/EP161431.OR"},{"key":"4510_CR25","doi-asserted-by":"crossref","unstructured":"25. Ignjatovi\u0107 Joci\u0107 V, Jankovi\u0107 Milju\u0161 J, I\u0161i\u0107 Den\u010di\u0107 T, \u017divaljevi\u0107 V, Tati\u0107 S, \u0110ori\u0107 I, et al. Expression of pY397-FAK and Its miR Regulators Drive Dedifferentiation in the Thyroid Neoplasia Spectrum. Cells. 2023;12(13).","DOI":"10.3390\/cells12131721"},{"key":"4510_CR26","doi-asserted-by":"crossref","unstructured":"26. Perdas E, Stawski R, Kaczka K, Zubrzycka M. Analysis of Let-7 Family miRNA in Plasma as Potential Predictive Biomarkers of Diagnosis for Papillary Thyroid Cancer. Diagnostics (Basel). 2020;10(3).","DOI":"10.3390\/diagnostics10030130"},{"key":"4510_CR27","doi-asserted-by":"crossref","unstructured":"27. Perdas E, Stawski R, Nowak D, Zubrzycka M. The Role of miRNA in Papillary Thyroid Cancer in the Context of miRNA Let-7 Family. Int J Mol Sci. 2016;17(6).","DOI":"10.3390\/ijms17060909"},{"key":"4510_CR28","doi-asserted-by":"crossref","unstructured":"28. Ricarte-Filho JC, Fuziwara CS, Yamashita AS, Rezende E, da-Silva MJ, Kimura ET. Effects of let-7 microRNA on Cell Growth and Differentiation of Papillary Thyroid Cancer. Transl Oncol. 2009;2(4):236\u2009\u2212\u200941.","DOI":"10.1593\/tlo.09151"},{"key":"4510_CR29","doi-asserted-by":"crossref","unstructured":"29. Van Branteghem C, Augenlicht A, Demetter P, Craciun L, Maenhaut C. Unraveling the Roles of miR-204-5p and HMGA2 in Papillary Thyroid Cancer Tumorigenesis. Int J Mol Sci. 2023;24(13).","DOI":"10.3390\/ijms241310764"},{"key":"4510_CR30","doi-asserted-by":"crossref","unstructured":"30. Rogucki M, Sidorkiewicz I, Niemira M, Dzi\u0119cio\u0142 JB, Buczy\u0144ska A, Adamska A, et al. Expression Profile and Diagnostic Significance of MicroRNAs in Papillary Thyroid Cancer. Cancers (Basel). 2022;14(11).","DOI":"10.3390\/cancers14112679"},{"key":"4510_CR31","doi-asserted-by":"crossref","unstructured":"31. Ding C, Yu H, Shi C, Shi T, Qin H, Cui Y. MiR-let-7e inhibits invasion and magration and regulates HMGB1 expression in papillary thyroid carcinoma. Biomed Pharmacother. 2019;110:528\u2009\u2212\u200936.","DOI":"10.1016\/j.biopha.2018.11.057"},{"key":"4510_CR32","doi-asserted-by":"crossref","unstructured":"32. Maggisano V, Capriglione F, Verrienti A, Celano M, Sponziello M, Pecce V, et al. Expression of miR-31-5p affects growth, migration and invasiveness of papillary thyroid cancer cells. Endocrine. 2023;79(3):517\u2009\u2212\u200926.","DOI":"10.1007\/s12020-022-03267-6"},{"key":"4510_CR33","doi-asserted-by":"crossref","unstructured":"33. Tomsic J, Fultz R, Liyanarachchi S, Genutis LK, Wang Y, Li W, et al. Variants in microRNA genes in familial papillary thyroid carcinoma. Oncotarget. 2017;8(4):6475-82.","DOI":"10.18632\/oncotarget.14129"},{"key":"4510_CR34","doi-asserted-by":"crossref","unstructured":"34. Geng X, Li Y, Sun Y, Cao L, Song Z. MicroRNA-181b-5p Facilitates Thyroid Cancer Growth via Targeting Programmed Cell Death 4. Mol Biotechnol. 2024;66(5):1154-64.","DOI":"10.1007\/s12033-023-01013-5"},{"key":"4510_CR35","doi-asserted-by":"crossref","unstructured":"35. Sun CX, Liu BJ, Su Y, Shi GW, Wang Y, Chi JF. MiR-181a promotes cell proliferation and migration through targeting KLF15 in papillary thyroid cancer. Clin Transl Oncol. 2022;24(1):66\u201375.","DOI":"10.1007\/s12094-021-02670-1"},{"key":"4510_CR36","doi-asserted-by":"crossref","unstructured":"36. Silaghi H, Pop LA, Georgescu CE, Muntean D, Cri\u0219an D, Silaghi P, et al. MicroRNA Expression Profiling-Potential Molecular Discrimination of Papillary Thyroid Carcinoma Subtypes. Biomedicines. 2024;12(1).","DOI":"10.3390\/biomedicines12010136"}],"container-title":["Endocrine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12020-025-04510-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12020-025-04510-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12020-025-04510-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:39:31Z","timestamp":1781638771000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12020-025-04510-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,9]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4510"],"URL":"https:\/\/doi.org\/10.1007\/s12020-025-04510-6","relation":{},"ISSN":["1559-0100"],"issn-type":[{"value":"1559-0100","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,9]]},"assertion":[{"value":"19 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 October 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"During the preparation of this work, the author(s) used ChatGPT (OpenAI) to assist with language refinement, grammar correction, and formatting of scientific writing. After using this tool, the author(s) reviewed and edited the content as needed and take full responsibility for the content of the publication.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The project was approved by the Institutional Review Board (IRB; CAAE number 44997215.1.0000.0065).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All patients who were being followed up at the institution\u2019s outpatient clinic completed the Informed Consent Form (ICF) at the time of their usual outpatient appointment. The IRB waived the requirement of the ICF for patients who died.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interests"}}],"article-number":"94"}}