MiRNA Deregulation Distinguishes Anaplastic Thyroid Carcinoma (ATC) and Supports Upregulation of Oncogene Expression

Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounting for the majority of thyroid cancer-associated deaths. Deregulation of microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating reorganization of the ATC transcriptome. Here, we applied comparative miRNA-/mRNA-sequencing in a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identifies 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline we unravel 85 prime miRNA-mRNA interactions supporting the downregulation of candidate tumor-suppressors and upregulation of bona fide oncogenes like survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provides a mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. Validation of deregulated protein expression in an independent thyroid carcinoma cohort demonstrates that miRNA-dependent oncogenes comprised in this signature, the transferrin receptor TFRC (CD71) and the E3-ubiquitin ligase DTL, are sharply upregulated in ATC. This upregulation is even sufficient to distinguish ATC from partially differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore key miRNA-mRNA regulation underlying the progression of thyroid carcinoma. Small RNA sequencing of the miRNA-transcriptome from 28 primary thyroid tumor samples