Cancer is one of the most common diseases affecting millions of people worldwide every year, representing the second leading cause of mortality after cardiovascular disease [1]. Uncontrolled cell growth due to genetic alterations [2], environmental factors [3] such as smoking [4], incorrect diet [5], obesity [6], infections [7], ionizing radiation [8], stress [9] and environmental pollutants [10] are the common denominators of each type of neoplasm. Especially, genetic alterations, which include chromosomal abnormalities and genetic mutations, represent one of the most noticeable causes [11] that contribute to tumorigenesis, affecting cell growth and metastases development [12].

Currently, although many conventional and innovative therapies are a valuable aid in the fight against cancer, the mortality rate remains high; in this context, late diagnosis represents one of the unfavorable factors [13]. Therefore, it is assumed that a precise and accurate search for diagnostic biomarkers can represent a turning point for cancer treatment by decreasing the poor prognosis in patients [14].

In the last decade, the diagnostic, prognostic, and therapeutic properties of microRNAs (miRNAs) have been investigated in many cancer types [15]. In fact, much evidence has demonstrated that miRNAs play important roles in tumorigenesis, development, and clinical therapy by acting as oncogenes or tumor-suppressor genes in various cellular processes such as tumor proliferation, apoptosis, angiogenesis, invasion, and metastasis [16].

Molecularly, miRNAs are small, endogenous, single-stranded, non-coding RNA molecules, approximately 20–22 nucleotides in length that originate from a stem-loop precursor [17].

The synthesis of mature miRNAs is a process that begins in the cell nucleus and completes in the cytoplasm, also involving highly specific enzymes [18]. Most miRNAs are transcribed by the RNA polymerase II complex, or to a lesser extent by RNA polymerase III [19], in a long primary polyadenylated transcript called pri-miRNA (100–1000 nt). The monocistronic pri-miRNA comprises a 7-methylguanosine cap at the 5′ end and a poly (A) tail at the 3′ end folded into a hairpin secondary structure consisting of a double-stranded stem, a erminal loop and two single-stranded segments parallel to the 3′ and 5′ ends [18]. The pri-miRNA, inside the cell nucleus, is split into smaller molecules (about 70–80 nucleotides), called pre-miRNA, from a very specific complex composed of the enzymes DGCR8 and Drosha (type III RNA-ase). The cut made by DGCR8 must be very precise to ensure the affinity of the miRNA for the target mRNA [18]. Successively, the pre-miRNA is transported into the cytosol by Exportin-5 protein (nucleus–cytoplasmic transporter) and Ran–Guanosine Triphosphate (Ran-GTP) cofactor and further cleaved by Dicer (type III RNase) [18] in a mature, short, double-stranded RNA (dsRNA) of about 22 nt. The dsRNA is bound by the Argonauta protein (Ago) and incorporated into the enzymatic complex called RISC (RNA-induced silencing complex), as a mature miRNA exercising its biological function [18].

miRNAs induce gene silencing by overlapping complementary sequences present on mRNA molecules; this overlap involves the repression of messenger translation and its degradation [20]. The silencing operated by an miRNA can occur through several mechanisms which may include the cleavage of the RNA molecule, or the destabilization of the RNA molecule by reducing the length of the polyA tail, or the decrease in the translation efficiency of the RNA molecule [21].

Most human miRNAs reside in the introns of genes or noncoding mRNA transcript regions [22], while other miRNAs are found within 3′ UTRs of mRNA genes, exons of noncoding mRNA genes, or are clustered with other miRNA genes [23]. miRNAs are evolutionarily conserved from worms to humans, and on the basis of the sequence homology at the 5′ end of the mature miRNAs can be clustered into families. A single miRNA can regulate as many as 200 gene targets different in their function, such as transcription factors, secreted factors, receptors, and transporters [24].

Thus, miRNAs form a complex monitoring network which, by negatively regulating the expression of their target genes at the post-transcriptional level, can control a wide variety of physiological functions [25].

Precisely for these properties, miRNAs have aroused considerable interest as prognostic markers and therapeutic targets for human neoplasms [26].

The members of the miR-19 family have identical seed regions and arise from two different paralogous clusters, miR-17-92 (miR-19a and miR-19b-1) and miR-106a-363 (miR-19-b-2) [27].

The miR-19 family plays an important role in regulating and maintaining tissue homeostasis and the normal development of organisms [27,28]. It has also been found that the miR-19 family contributes to the homeostatic maintenance of the immune system, specifically lymphocytes, the regulation of the differentiation of follicular helper T cells [29], and the modulation of the development of B cells [30]. Some evidence suggests that the miR-19 family is implicated in regulating inflammation, tissue fibrosis, aging, metabolism, and tumorigenesis [27].

Moreover, members of the miR-19 family contribute to regulating the development of the nervous system, respiratory systems, cardiovascular systems, blood vessel formation, vertebrate axis, etc. Accordingly, their dysregulation often results in various diseases, and even cancer [27].

Among miR-19 family members, miR-19a is the most well-known oncogenic miRNA [31], and its oncogenic activity results in promoting c-MYC-induced lymphomagenesis by repressing apoptosis and the tumor suppressor phosphatase and tensin homolog (PTEN) [31]. Furthermore, miR-19a activates the protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, thereby functionally antagonizing PTEN to promote cell survival [31].

PTEN targeted by miR-19a [32], and more specifically of PTEN/AKT signaling [33,34], also induces tumor cells’ resistance to chemotherapeutic agents. Chemoresistance is the primary cause of treatment failure in cancer patients [35] and it is attributed to various aspects, including diminished drug accumulation and drug–target interaction, increased tumor stem cell populations and autophagic activity, and reduced apoptotic processes in cancer cells [35].

miR-19a has been shown to alter cellular sensitivity to chemotherapy drugs, including the well-known cisplatin, 5-Fluorouracil and Adriamycin, and to upregulate the expression of P-glycoprotein (P-gp), critical in the management of cytotoxic drug efflux [36].

Therefore, it is also clear that in this circumstance, the control of miR-19a levels could contribute to positive outcomes for cancer patients.

Moreover, several studies have identified thousands of circular RNAs (circRNAs) in various organisms, denoting their importance in various pathophysiological processes [37]. Indeed, circRNAs have the ability to regulate gene expression by affecting transcription, mRNA turnover, and also translation by sponging RNA-binding proteins and miRNAs [37].

Consequently, given the wide correlation between circRNAs on miRNA activity, several studies, especially in the oncology field, have investigated the impact of miRNA sponging by circRNA on gene regulation [38,39]. In this context, innovative methods for its molecular detection can play a key role in multiple identifications and data correlation, providing important oncology research advancements.

2. Roles and Mechanisms of Action of miR-19a in Clinical Cancer Features