Abstract
The alteration of miRNA processing is a driver event in several tumors including thyroid cancer. In particular, somatic DICER1 mutations, reported in follicular-patterned lesions, are shared by benign as well as malignant tumors. In the present study, we investigated the effects of alterations in the miRNA processing genes on the miRNA profile.The study included 19 follicular adenomas (FAs) and 22 follicular variant of papillary thyroid carcinomas (FVPTCs). The mutational status in the hot spot regions of DICER1, DROSHA, TARBP2, DGCR8 and the most commonly affected genes in thyroid tumors was investigated on both tumor and paired normal tissues. The miRNA profile and the mRNA expression levels of DICER1, DROSHA, TARBP2, DGCR8 and XPO5 were also evaluated.Two DICER1 RNase IIIb domain mutations were found in FAs. These lesions presented a considerable loss of 5p miRNAs. Fifteen miRNAs were specifically deregulated in DICER1-mutant lesions compared to FAs and FVPTCs. These miRNAs regulate crucial pathways in cancer such as Hippo, p53 and TGF-beta signalling.DICER1 somatic mutations in the RNase IIIb domain are not specific for malignancy, but the miRNA imbalance that they cause is remarkable, especially with regard to the loss of 5p miRNAs. DICER1-mutant lesions have a characteristic miRNA deregulation, which is different from that of FVPTCs; nevertheless, this impairment is consistent with malignant transformation. Further studies providing the real risk of malignancy associated with DICER1 mutations and the evolution of DICER1-mutant lesions are needed to make them useful in the clinical practice.
Highlights
The biogenesis of microRNAs occurs in the nucleus and in the cytoplasm
There were no differences between follicular adenomas (FAs) and follicular variant of papillary thyroid carcinomas (FVPTCs) in terms of gender, age and size
In the deep sequencing era, there is an urgent need for the discovered mutations to be contextualized so that they may be helpful in the clinical practice
Summary
Pre-miRNAs exit the nucleus by exportin 5 (XPO5), and in the cytoplasm they undergo further processing by the ribonuclease DICER1 and the RNA binding protein TARBP2 (TARBP2, RISC loading complex RNA binding subunit) [1]. This step produces mature miRNAs that will be assembled in the RNA-induced silencing complex in order to silence the expression of specific targets by translational repression, mRNA deadenylation and decay [2]. In other tumors such as lung, skin and breast cancers, low levels of DICER1 mRNA or protein are associated with malignant lesions and poor prognosis [1]
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