*2.4. RNA Alterations*

It is universally recognized that messenger RNA (mRNA) synthesis and translation are deeply modified in cancer; however, new evidence shows that all kinds of RNA are universally impaired [49]. In normal condition, cells produce different types of RNAs: mRNA, ribosomal RNA (rRNA), transfer RNA (tRNA), microRNA (miRNA), long non-coding (lncRNA) and circular RNA (circRNA). Accordingly, neoplastic cells could deregulate all kinds of RNAs that could promote the cells growth and invasiveness [49].

In particular, miRNA are usually 20–23 nucleotides in length that can bind multiple mRNA, regulating their catabolism and further their translation [50]. 127 and 18 different miRNAs have been characterized in ATC and PDTC, respectively. Among them, 69 miRNAs resulted decreased and 54 increased in ATC, while 10 resulted decreased and

8 increased in PDTC. If their role in PDTC is not fully elucidated and they might be used as an ancillary diagnostic tool and prognostic marker [51], they have been fully characterized in ATC. According to literature data, we grouped them into 3 main roles: regulation of growth tumor, invasiveness and resistance to therapy (Figure 2). We found that 9 miRNA were related to tumor growth [52–61], 14 to tumor growth and invasiveness [62–69], 28 to invasiveness [67,70–76], and 66 to therapies resistance (62 to anti-BRAF treatment, 3 to chemotherapy and 1 to radiotherapy) [77–81]. Additionally, 10 miRNAs were considered as an ancillary diagnostic tool [82,83] (Figure 2).

**Figure 2.** miRNA that were discovered in ATC according to their function.

Beyond miRNA, growing evidence is showing the role of lncRNAs in cancer. lncRNA are RNAs longer than 200 nucleotides that do not encode proteins but regulate gene expression, splicing and nucleation of subnuclear domains [49]; moreover, lncRNAs may have cytoplasmic functions, such as miRNA sponging, interaction with signaling proteins, and further modulation of mRNA translation [49]. In ATC, lncRNAs may regulate tumor growth [84,85], invasiveness [86], and both tumor growth and invasiveness [87–91]; they can also regulate cancer sensitivity to treatments [92]. In particular, lncRNA PTCSC3 was described at low levels both in ATC tissue and cell lines and it was demonstrated that its upregulation inhibited the resistance to doxorubicin by suppressing stem cell proprieties [92].

Finally, circRNAs are usually consequence of back-splicing events, producing in a covalently closed circRNA molecule instead of linear ones. Although circRNAs have usually been detected at low levels in normal and in cancer cells, some of them are at higher concentration and have functional roles: miRNA sponging and proteins stabilization [49]. In ATC, a recent study showed that circRNA may produce resistance to chemotherapy. In particular, Liu et al. showed that circRNA EIF6 could sponge miR-144-3p to promote autophagy and cisplatin-resistance [93].
