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

Danny Misiak,Marcus Bauer,Jacob Haase,Stefan Hüttelmaier,Jana Lange,Juliane Braun,Kerstin Lorenz,Claudia Wickenhauser

doi:10.3390/cancers13235913

Abstract

Simple SummaryMicroRNAs are essential regulators of gene expression. Their deregulation is associated with a substantial reorganization of the transcriptome in anaplastic thyroid carcinoma (ATC). Here, we present an integrated, combinatorial approach based on miRNA–mRNA sequencing to unravel miRNA–mRNA networks deregulated in ATC. We identify miRNA–mRNA signatures sharply distinguishing ATC and uncover prime oncogenes upregulated by the downregulation of miRNAs in ATC.Anaplastic thyroid carcinoma (ATC) is the most fatal and rapidly evolving endocrine malignancy invading the head and neck region and accounts for up to 50% of thyroid cancer-associated deaths. Deregulation of the microRNA (miRNA) expression promotes thyroid carcinoma progression by modulating the reorganization of the ATC transcriptome. Here, we applied comparative miRNA–mRNA sequencing on a cohort of 28 thyroid carcinomas to unravel the association of deregulated miRNA and mRNA expression. This identified 85 miRNAs significantly deregulated in ATC. By establishing a new analysis pipeline, we unraveled 85 prime miRNA–mRNA interactions supporting the downregulation of candidate tumor suppressors and the upregulation of bona fide oncogenes such as survivin (BIRC5) in ATC. This miRNA-dependent reprogramming of the ATC transcriptome provided an mRNA signature comprising 65 genes sharply distinguishing ATC from other thyroid carcinomas. The validation of the 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 sufficient to distinguish ATC even from poorly differentiated thyroid carcinomas (PDTC). In sum, these findings provide new diagnostic tools and a robust resource to explore the key miRNA–mRNA regulation underlying the progression of thyroid carcinoma.

Highlights

Thyroid cancer of follicular origin is the most common endocrine malignancy, with significantly increasing incidence
We identified cancer hallmarks likely controlled by miRNA deregulation in Anaplastic thyroid carcinoma (ATC) and demonstrated that the downregulation of miRNAs is associated with a severe upregulation of oncogenes such as survivin (BIRC5)
The comparison of miRNAs in ATC compared to all other WDTC and NT samples, which are collectively referred to as “others”, revealed an ATC-specific miRNA deregulation

Summary

Introduction

Thyroid cancer of follicular origin is the most common endocrine malignancy, with significantly increasing incidence. These occur in WDTCs at variable incidence and frequency [6] These somatic mutations largely fail to provide a sufficient basis for the tremendous reorganization of the ATC transcriptome, recently deciphered by the comparative mRNA sequencing of ATC, WDTC (FTC and PTC) as well as nonmalignant thyroid samples [8]. These studies indicated that compared to ATC, WDTCs show a rather moderate change in gene expression in contrast to nonmalignant thyroid carcinomas.

Objectives

Methods

Results

Conclusion