MicroRNA signature of thyroid tumors and its possible diagnostic application for the differential diagnosis of follicular thyroid cancer and follicular adenomas
Zusammenfassung der Projektergebnisse
The differentiation of the rarely occurring thyroid carcinoma from the frequently occurring benign thyroid nodules is a clinically important, frequent and challenging issue. Fine-needle aspiration cytology (FNAC) is a very sensitive and specific tool for the differential diagnosis of thyroid nodules. However, it reveals the inconclusive result of follicular proliferation (characteristic for both follicular thyroid carcinoma (FTCs) and follicular adenoma (FAs)) in up to 20%. Furthermore, the knowledge of the molecular etiology of FAs which comprise approximately 85% of thyroid nodules and which are characterized by increased proliferation is still very limited. Since a profound knowledge of the molecular etiology of both FAs and FTCs is a prerequisite for a better differential diagnosis of both tumors the first aim of the project was to improve the knowledge of the molecular etiology of both FAs and FTCs. In previous studies we could show a significantly increased proliferation in benign cold thyroid nodules (CTNs) and we could identify the molecular pattern of this increased proliferation, which is characterized by a differential mRNA expression of several cell cycle associated genes. In the present project we could further delineate the molecular background of the increased proliferation by the identification of differentially expressed miRNAs. Our approach of combining the mRNA and miRNA expression data allowed us to identify novel interactions between miRNAs and mRNAs that contribute to the phenotype of CTNs. We could show that downregulation of miR-31 promotes tumorigenesis by dedifferentiating and proliferation stimulating mechanisms by increasing cyclin D1 expression and modulating cell cycle progression. MiR-130b on the other hand, increases apoptosis in CTNs and is a putative compensatory mechanism for the increased proliferation rate. The comparison of FTCs and their normal surrounding tissues revealed miRs-146b, -183, and -221 to be differentially up-regulated and miR-199b to be differentially down-regulated in FTCs. Cell culture experiments demonstrated that miR-183 and miR-146b overexpression stimulates migration. Moreover, the overexpression of miR-183 led to a reduced apoptosis rate. The comparison of the mRNA expression patterns of FTCs and FAs revealed a simple 5- gene classifier that can distinguish FTCs from FAs with good accuracy, comparable to currently marketed diagnostic tools. It is based on the 2 largest FTC-FA microarray datasets and was validated on an independent FFPE sample set, with a sensitivity of up to 90%. In the future, such a molecular test may serve as an important tool for assisting pathologists in cases of thyroid follicular neoplasms where a clear clinical decision cannot be made based on histopathology. Moreover its application for indeterminate FNA samples needs to be investigated. In summary, by analyzing the miRNA expression patterns of FAs (i.e., CTNs) and FTCs in comparison to their respective normal surrounding tissues, we identified specific miRNAs, whose functional characterization contributes to further explain the phenotype of these thyroid tumors and represents a further step towards improving our knowledge of the etiology of FAs and FTCs. In ongoing studies we compare the miRNA expression patterns of FTCs and FAs to identify potential diagnostically relevant markers and classifiers, which might help to improve the differential diagnosis of FTCs and FAs by the molecular analysis of fine needle aspirates.
Projektbezogene Publikationen (Auswahl)
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2013. Inverse correlation of miRNA and cell cycle-associated genes suggests influence of miRNA on benign thyroid nodule tumorigenesis. J Clin Endocrinol Metab 98(1):E8-16
Ferraz C, Lorenz S, Wojtas B, Bornstein SR, Paschke R, Eszlinger M
