Mechanisms and role of microRNA deregulation in cancer onset and progression

Abstract

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20–23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5′ end (‘seed’ region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3′ UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms.

The biology of personalized cancer medicine: Facing individual complexities underlying hallmark capabilities

“…Although attenuated expression of the miRNA transcriptome is frequently observed (Kumar et al., 2007; Lu et al., 2005), various miRNAs are overexpressed in specific tumors compared to their healthy tissue of origin (Ma et al., 2010a,b; Volinia et al., 2006), and thus are termed “oncomiRs”. Furthermore, the predicted targets for several cancer‐associated miRNAs include protein‐coding tumor suppressors and oncogenes, supporting a role for miRNAs in cancer pathogenesis (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011). The rapid implementation of miRNA profiling techniques (such as miRNA SAGE, microarray and deep‐sequencing) has helped in defining “miRNA gene signatures” for many cancer types, and several miRNAs now represent robust disease‐specific predictive and prognostic biomarkers (Kasinski and Slack, 2011).…”

“…miRNAs are small RNAs that finely tune the expression of multiple target genes; altered miRNA expression has been observed in a variety of human pathological conditions, including cancer (Bartel, 2009). The function of miRNAs may be deregulated in cancer in several manners, including miRNA gene mutation, deletion or promoter hypermethylation, but also as a consequence of mutations in their target sequences (Esquela‐Kerscher and Slack, 2006; Nana‐Sinkam and Croce, 2011; Palmero et al., 2011). Although attenuated expression of the miRNA transcriptome is frequently observed (Kumar et al., 2007; Lu et al., 2005), various miRNAs are overexpressed in specific tumors compared to their healthy tissue of origin (Ma et al., 2010a,b; Volinia et al., 2006), and thus are termed “oncomiRs”.…”

“…miRNA signatures can also be identified in the peripheral circulation of cancer patients (Mitchell et al., 2008), and several tumor‐associated miRNAs have been isolated from circulating microvesicles and exosomes (Rani et al., 2011). Of note, miRNAs are relatively stable compared to mRNAs and can be profiled from paraffin‐embedded tissues and body fluids such as blood and urine (Palmero et al., 2011; Wittmann and Jack, 2010). …”

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

“…[96][97][98] Alterations in miRNA expression have been demonstrated to be associated with numerous human pathologies, including cancer, where miRNAs have been demonstrated to be involved in tumororigenesis and progression, behaving as tumor-promoting miRNAs (oncomiRNAs) or alternatively as tumor suppressor miRNAs ( Figure 5). [99][100][101][102][103][104] As a result, several antagonists of miRNAs or miRNA mimics have shown activity in preclinical cancer models, and several have advanced into clinical testing (see Table 2). …”

O papel dos microRNAs de células T na susceptibilidade/resistência a artrite reumatóide experimental

“…Assim, não é surpresa que os microRNAs tenham um papel importante em muitas condições patológicas, das quais o câncer é uma das mais bem estudadas (MEDINA & SLACK, 2008;PALMERO et al, 2011). É muito claro, que a regulação apropriada exercida pelos microRNAs é crítica para as funções normais do sistema imune, evitando o desenvolvimento de autoimunidade.…”