Effects of AntagomiRs on Different Lung Diseases in Human, Cellular, and Animal Models

Murdaca, Giuseppe; Tonacci, Alessandro; Negrini, Simone; Greco, Monica; Borro, Matteo; Puppo, Francesco; Gangemi, Sebastiano

MicroRNAs (miRNAs) are small molecules made of 21 nucleotides, which modulate several biological processes through post-transcriptional gene expression regulation [1] . In addition, many miRNA knockout strains have differential responses to models of several disorders such as neuronal, cardiac, pulmonary, vascular, renal, immunological, while some of them have altered susceptibility to fungal or bacterial infections, or altered propensity to develop tumors in cancer models [2] . In fact, miRNAs may control tumor development, both acting as tumor-promoting miRNAs (oncomiRNAs and metastamiRNAs) or as tumor suppressor miRNAs [3, 4] . Furthermore, it was demonstrated that several human miRNAs are located in specific genomic sites which are involved in cancer [5] . During the last decade, researchers investigated miRNAs functioning and regulation. More recently, they focused on miRNA stability and turnover. Indeed, it was established that miRNAs are very dynamic molecules, presenting with a rapid turnover, which depends on their activation. On these bases, researchers investigated miRNA-induced silencing complex (miRISC) and Argonaute (AGO) proteins, which directly interact with miRNAs and are key factors in the assembly and function of Int. J. Mol. Sci. 2019, 20, 3938 2 of 32 miRISCs [1] . In order to act on miRNAs turnover, antagomiRs have been developed. They are a novel class of chemically engineered oligonucleotides, which are specific silencers of endogenous miRNAs. Specifically, two major molecular changings have been developed in order to increase chemical stability. Thus, including switching of the phosphodiester support with a phosphorothioate linkage between nucleotides or including a 2 O-methyl group. Additionally, antagomiRs with a cholesterol moiety are thought to promote cellular uptake [6] . Considering the complex role of miRNAs, these new molecules can be powerful tools to silence specific miRNAs in vivo and may represent a therapeutic strategy for silencing miRNAs in disease. Indeed, Krützfeldt et al. [7] conducted a study on mice in order to study the biological significance of miR-122, which is abundant in the liver. Analysis of gene expression of messenger RNA from antagomiR-treated animals disclosed that the 3 untranslated areas of upregulated genes were extremely enriched with miR-122 recognition motives, while down-regulated genes were poor of these motives. Moreover, researchers found that cholesterol biosynthesis genes would have been modulated by miR-122; in fact, plasma cholesterol levels were reduced in antagomiR-122-treated mice. So far, evidence on antagomiR function has been collected on cellular, animal, and human models. Moreover, as described below, data in these three groups are often coherent. This in support of the hypothesis that miRNAs are molecular factors capable of influencing the expression of several disorders. To date, new studies regarding the use of miRNAs as therapeutic targets are ongoing, especially in the treatment of HCV infection, atherosclerosis, and oncologic diseases. As Gambari et al. [3] highlighted in their review, until now, several antagomiRs have been studied among oncologic diseases as therapeutic agents, both alone or in combination with standard drugs. The promising results explain the reason why these agents will improve the therapy of several tumors, such as gastric cancer, gliomas, and breast cancer [8] [9] [10] . Indeed, the role of miRNAs upon lung disorders has been ext