{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T23:50:52Z","timestamp":1782863452013,"version":"3.54.5"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyroid cancer is the most common endocrine malignancy, and preoperative distinction between benign and malignant nodules remains challenging, especially in cytologically indeterminate cases. Circulating microRNAs (miRNAs) have gained interest as non-invasive biomarkers due to their stability and involvement in tumorigenesis. This study aimed to assess the preoperative diagnostic value of circulating miR-146a and miR-221 in patients undergoing thyroidectomy. A total of 56 patients were included, of whom 24 had malignant and 32 had benign thyroid lesions confirmed by histopathology. Preoperative plasma levels of miR-146a and miR-221 were quantified using qRT-PCR, and relative expression was calculated with the 2\u2212\u0394\u0394Ct method. miR-221 expression was significantly higher in malignant cases, with an area under the ROC curve of 1.00, achieving 100% sensitivity and specificity at the optimal threshold. miR-146a showed no significant discriminatory ability. Weak correlations were observed between miRNA expression and clinical parameters such as age, TIRADS score, or thyroid volume. Logistic regression including miR-221 led to perfect separation, indicating strong predictive capacity but precluding multivariate modeling. These findings suggest that circulating miR-221 may serve as a highly accurate biomarker for thyroid malignancy and warrant further validation in larger, prospective cohorts.<\/jats:p>","DOI":"10.3390\/ijms26157564","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Preoperative Expression Profiles of miR-146a and miR-221 as Potential Biomarkers for Differentiating Benign from Malignant Thyroid Nodules"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5042-5539","authenticated-orcid":false,"given":"Mervat","family":"Matei","sequence":"first","affiliation":[{"name":"Department of Doctoral Studies, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0854-8164","authenticated-orcid":false,"given":"Sergiu-Ciprian","family":"Matei","sequence":"additional","affiliation":[{"name":"Abdominal Surgery and Phlebology Research Center, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"1st Surgical Department, Pius Br\u00eenzeu Emergency County Hospital, 300723 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8933-3060","authenticated-orcid":false,"given":"Cristina Stefania","family":"Dumitru","sequence":"additional","affiliation":[{"name":"Department II of Microscopic Morphology, Discipline of Histology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, E. Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9387-1141","authenticated-orcid":false,"given":"Roxana","family":"Popescu","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Biology, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"},{"name":"ANAPATMOL Research Center, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Tudor Vladimirescu Street, No. 14, 300174 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3138-3051","authenticated-orcid":false,"given":"Ligia","family":"Petrica","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II\u2014Nephrology University Clinic, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania"},{"name":"Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6032-6246","authenticated-orcid":false,"given":"Ioana","family":"Golu","sequence":"additional","affiliation":[{"name":"Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania"},{"name":"2nd Department of Internal Medicine\u2014Endocrinology Clinic, \u201cVictor Babes\u201d University of Medicine and Pharmacy, P-Ta Eftimie Murgu 2, 300041 Timisoara, Romania"},{"name":"Department of Endocrinology, County Emergency Hospital Timisoara, Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marioara","family":"Cornianu","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology-Morphopatology, ANAPATMOL Research Center, \u201cVictor Babes\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella Ionela","family":"Stoian","sequence":"additional","affiliation":[{"name":"Department of Microscopic Morphology, \u201cVictor Babe\u015f\u201d University of Medicine and Pharmacy, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-1650","authenticated-orcid":false,"given":"Mihaela Maria","family":"Vlad","sequence":"additional","affiliation":[{"name":"Centre for Molecular Research in Nephrology and Vascular Disease, Faculty of Medicine, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania"},{"name":"2nd Department of Internal Medicine\u2014Endocrinology Clinic, \u201cVictor Babes\u201d University of Medicine and Pharmacy, P-Ta Eftimie Murgu 2, 300041 Timisoara, Romania"},{"name":"Department of Endocrinology, County Emergency Hospital Timisoara, Blvd. Liviu Rebreanu 156, 300723 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1097\/CM9.0000000000003284","article-title":"Global Burden of Thyroid Cancer in 2022: Incidence and Mortality Estimates from GLOBOCAN","volume":"137","author":"Lyu","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ali, S.Z., and VanderLaan, P.A. (2023). Papillary Thyroid Carcinoma, Subtypes, and Related Tumors. The Bethesda System for Reporting Thyroid Cytopathology, Springer.","DOI":"10.1007\/978-3-031-28046-7"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/cncy.21631","article-title":"Impact of Reclassifying Noninvasive Follicular Variant of Papillary Thyroid Carcinoma on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology","volume":"124","author":"Faquin","year":"2016","journal-title":"Cancer Cytopathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1038\/s41388-024-03076-3","article-title":"MicroRNAs: Circulating Biomarkers for the Early Detection of Imperceptible Cancers via Biosensor and Machine-Learning Advances","volume":"43","author":"Metcalf","year":"2024","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1002\/jcp.27486","article-title":"An Overview of MicroRNAs: Biology, Functions, Therapeutics, and Analysis Methods","volume":"234","author":"Saliminejad","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"229","DOI":"10.4103\/0973-029X.140762","article-title":"MicroRNAs\u2014Biology and Clinical Applications","volume":"18","author":"Ranganathan","year":"2014","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ali Syeda, Z., Langden, S.S.S., Munkhzul, C., Lee, M., and Song, S.J. (2020). Regulatory Mechanism of MicroRNA Expression in Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051723"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Gayt\u00e1n-Pacheco, N., Ib\u00e1\u00f1ez-Salazar, A., Herrera-Van Oostdam, A.S., Oropeza-Valdez, J.J., Maga\u00f1a-Aquino, M., L\u00f3pez, J.A., Mon\u00e1rrez-Espino, J., and L\u00f3pez-Hern\u00e1ndez, Y. (2022). miR-146a, miR-221, and miR-155 are Involved in Inflammatory Immune Response in Severe COVID-19 Patients. Diagnostics, 13.","DOI":"10.3390\/diagnostics13010133"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fr\u00fcndt, T., Krause, L., Hussey, E., Steinbach, B., K\u00f6hler, D., von Felden, J., Schulze, K., Lohse, A.W., Wege, H., and Schwarzenbach, H. (2021). Diagnostic and Prognostic Value of miR-16, miR-146a, miR-192 and miR-221 in Exosomes of Hepatocellular Carcinoma and Liver Cirrhosis Patients. Cancers, 13.","DOI":"10.3390\/cancers13102484"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Condrat, C.E., Thompson, D.C., Barbu, M.G., Bugnar, O.L., Boboc, A., Cretoiu, D., Suciu, N., Cretoiu, S.M., and Voinea, S.C. (2020). miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis. Cells, 9.","DOI":"10.3390\/cells9020276"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zhang, C., Sun, C., Zhao, Y., Wang, Q., Guo, J., Ye, B., and Yu, G. (2022). Overview of MicroRNAs as Diagnostic and Prognostic Biomarkers for High-Incidence Cancers in 2021. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911389"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s40618-017-0735-6","article-title":"The Role of MicroRNAs in Different Types of Thyroid Carcinoma: A Comprehensive Analysis to Find New miRNA Supplementary Therapies","volume":"41","author":"Pishkari","year":"2018","journal-title":"J. Endocrinol. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3360","DOI":"10.1007\/s12032-012-0315-8","article-title":"Overexpression of miR-221 Is Associated with Aggressive Clinicopathologic Characteristics and the BRAF Mutation in Papillary Thyroid Carcinomas","volume":"29","author":"Zhou","year":"2012","journal-title":"Med. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.32604\/or.2024.049235","article-title":"MicroRNAs in Thyroid Cancer with Focus on Medullary Thyroid Carcinoma: Potential Therapeutic Targets and Diagnostic\/Prognostic Markers and Web Based Tools","volume":"32","author":"Shakiba","year":"2024","journal-title":"Oncol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kondrotien\u0117, A., Dauk\u0161a, A., Pamedytyt\u0117, D., Kazokait\u0117, M., \u017dvirblien\u0117, A., Dauk\u0161ien\u0117, D., Simanavi\u010dien\u0117, V., Klimait\u0117, R., Golubickait\u0117, I., and Stakaitis, R. (2020). Plasma-Derived miRNA-222 as a Candidate Marker for Papillary Thyroid Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176445"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cai, S., Ma, J., Wang, Y., Cai, Y., Xie, L., Chen, X., Yang, Y., and Peng, Q. (2022). Biomarker Value of miR-221 and miR-222 as Potential Substrates in the Differential Diagnosis of Papillary Thyroid Cancer Based on Data Synthesis and Bioinformatics Approach. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.794490"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4252","DOI":"10.3892\/ol.2017.6028","article-title":"Dynamic Monitoring of Circulating MicroRNAs as a Predictive Biomarker for the Diagnosis and Recurrence of Papillary Thyroid Carcinoma","volume":"13","author":"Zhang","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12957-016-1086-z","article-title":"miR-221, a Potential Prognostic Biomarker for Recurrence in Papillary Thyroid Cancer","volume":"15","author":"Dai","year":"2017","journal-title":"World J. Surg. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.2147\/OTT.S190364","article-title":"MicroRNA-221 promotes papillary thyroid carcinoma cell migration and invasion via targeting RECK and regulating epithelial-mesenchymal transition","volume":"12","author":"Wei","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, G., Santonocito, R., Grech, G., Graceffa, G., Cipolla, C., Scalia, F., Raccosta, S., Manno, M., Conway de Macario, E., and Macario, A.J.L. (2024). MiRNAs in Extracellular Vesicles as Biomarkers in Plasma of Papillary Thyroid Cancer Patients: A Proof-of-Concept Study. Biology, 13.","DOI":"10.3390\/biology13090743"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5651","DOI":"10.1038\/onc.2008.178","article-title":"MiR-221 controls CDKN1C\/p57 and CDKN1B\/p27 expression in human hepatocellular carcinoma","volume":"27","author":"Fornari","year":"2008","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1186\/1756-6614-4-S1-S1","article-title":"Pathogenic mechanisms of deregulated microRNA expression in thyroid carcinomas of follicular origin","volume":"4","author":"Braun","year":"2011","journal-title":"Thyroid Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rezaei, M., Khamaneh, A.M., Zarghami, N., Vosoughi, A., and Hashemzadeh, S. (2019). Evaluating pre- and post-operation plasma miRNAs of papillary thyroid carcinoma (PTC) patients in comparison to benign nodules. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5849-0"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1210\/jc.2011-1004","article-title":"MicroRNAs in thyroid cancer","volume":"96","author":"Jazdzewski","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"52475","DOI":"10.18632\/oncotarget.9655","article-title":"miRNA expression and function in thyroid carcinomas: A comparative and critical analysis and a model for other cancers","volume":"7","author":"Saiselet","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"155050","DOI":"10.1016\/j.prp.2023.155050","article-title":"Role of microRNA-146a in cancer development by regulating apoptosis","volume":"254","author":"Kookli","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Matei, M., Vlad, M.M., Golu, I., Dumitru, C.\u0218., De Scisciolo, G., and Matei, S.-C. (2023). Can Routine Laboratory Tests Be Suggestive in Determining Suspicions of Malignancy in the Case of Thyroid Nodules?. Medicina, 59.","DOI":"10.3390\/medicina59081488"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1533","DOI":"10.1002\/wrna.1533","article-title":"miR-146a-5p: Expression, regulation, and functions in cancer","volume":"10","author":"Iacona","year":"2019","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_29","unstructured":"Biello, A., Kinberg, E.C., Menon, G., and Wirtz, E.D. (2025, July 11). Thyroidectomy, StatPearls, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK563279\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.1097\/SLA.0000000000003580","article-title":"The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults","volume":"271","author":"Patel","year":"2020","journal-title":"Ann. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e230067","DOI":"10.1530\/ETJ-23-0067","article-title":"2023 European Thyroid Association Clinical Practice Guidelines for thyroid nodule management","volume":"12","author":"Durante","year":"2023","journal-title":"Eur. Thyroid J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1507\/endocrj.EJ24-0644","article-title":"The 2024 revised clinical guidelines on the management of thyroid tumors by the Japan Association of Endocrine Surgery","volume":"72","author":"Sugitani","year":"2025","journal-title":"Endocr. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1007\/s13304-023-01522-7","article-title":"Management of surgical diseases of thyroid gland: Indications of the United Italian Society of Endocrine Surgery (SIUEC)","volume":"75","author":"Polistena","year":"2023","journal-title":"Updat. Surg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:23:37Z","timestamp":1760034217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157564"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157564","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,5]]}}}