o:30306 Expression of pY397-FAK and Its miR Regulators Drive Dedifferentiation in the Thyroid Neoplasia Spectrum Ekspresija pY397-FAK i njenih mikroRNK regulatora vodi ka dediferencijaciji u spektru tiroidnih neoplazija en ABSTRACT Thyroid carcinomas are growing malignancies worldwide. They encompass several diagnostic categories with varying degrees of dedifferentiation. Focal adhesion kinase is involved in cellular communication and locomotion. It is regulated on a posttranscriptional level by miR-7, miR-135a, and miR-138 and on a posttranslational level by autophosphorylation at Y397 (pY397-FAK). We related regulators of FAK with histologic dedifferentiation, clinicopathological factors, and differential diagnosis in the thyroid neoplasia spectrum. We classified 82 cases into 5 groups with increasing aggressiveness: healthy tissue, follicular and classical variants of papillary thyroid carcinoma (PTC), dedifferentiated PTC, and anaplastic carcinoma. MiRs were analyzed by RT-qPCR. Protein expression of pY397-FAK was analyzed by immunohistochemistry (separately in the membrane, cytoplasm, and nuclear compartment) and Western blot. All three miRs were upregulated in healthy tissue compared to malignant, while pY397-FAK was downregulated. MiRs and pY397-FAK were not mutually correlated. MiR-135a-5p was decreasing while membranous and cytoplasmic pY397-FAK increased with dedifferentiation. Neither miR correlated with clinicopathological factors. MiR-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK discriminated the follicular from the classical variant of PTC. Disturbances of FAK regulation on different levels contribute to neoplastic dedifferentiation. pY397-FAK exerts its oncogenic role in the membrane and cytoplasm. Diagnostically, miRs-135a-5p, miR-138-5p, and membranous and cytoplasmic pY397-FAK differentiated between classical and follicular PTC. pY397-FAK, miRs, thyroid carcinoma, neoplastic dedifferentiation, differential diagnostics 1552099 10.3390/cells12131721 2023-06-29T20:16:09.235Z 44 yes 46 Valentina Ignjatović Jocić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia 0000-0002-9887-4237 Jelena Janković Miljuš University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor biohemijskih nauka person 0000-0002-2589-3306 Tijana Išić Denčić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka person 0000-0001-8475-2266 Vladan Živaljević University Clinical Center of Serbia, Center for Endocrine Surgery, Belgrade, Serbia person Svetislav Tatić University of Belgrade, Faculty of Medicine, Institute for Pathology, Serbia person Ilona Đorić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka person 0000-0001-5322-4559 Sonja Šelemetjev University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka person 0000-0002-2898-6671 application/pdf 2079267 https://phaidrabg.bg.ac.rs/o:30306 no yes 16 70 92000001 11A29 11A2902 11A32 11A3240 Cells 12 13 MDPI 2023