MicroRNA signature of thyroid tumors and its possible diagnostic application

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 20 – 30% of FNACs. 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, one of our aims is 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. More recently, 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 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.

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.