MicroRNA and cancer – A brief overview
Introduction
MicroRNAs (miRNAs) are short non-coding RNAs of ∼22 nucleotides found in all eucariotic cells, which play important roles in almost all biological pathways (Jansson and Lund, 2012). In 1993 two independent studies identified the Caenorhabditis elegans heterochronic gene lin-4 as a small non-coding RNA (ncRNA) (Lee et al., 1993, Wightman et al., 1993). After a gap of seven years it was shown that the C. elegans heterochronic gene, let-7, together with lin-4 RNA was capable to start the temporal cascade of regulatory heterochronic genes (Reinhart et al., 2000). Since then many laboratories have focused their research on the study of these small non-coding RNAs, providing evidence for the existence of a large class of small ncRNAs with regulatory roles which were named microRNAs (Lagos-Quintana et al., 2001, Lau et al., 2001, Lee and Ambros, 2001). In fact, the miRNA database (miRBase), released in June 2014, shows 2588 mature miRNAs in humans, and approximately 1915 in mice. It has been estimated that miRNAs regulate ∼60% of human genes (Bartel, 2009). They are implicated in biological processes such as cell cycle control (Carleton et al., 2007), apoptosis (Jovanovic and Hengartner, 2006), metabolism (Boehm and Slack, 2006) and development and differentiation (Harfe, 2005). They have been shown to be also involved in many diseases such as neurodegenerative (Jin et al., 2004) and metabolic disorders (Poy et al., 2004) as well as cancer (Lu et al., 2005, Volinia et al., 2006). In 2002 the first association between miRNA deregulation and cancer was found by studying a critical region at chromosome 13q14, frequently deleted in CLL. It came to light that this region contains two microRNA genes, miR-15a and miR-16-1, expressed in the same polycistronic RNA. The deletion of these two important miRNAs causes the development of the indolent form of CLL (Calin et al., 2002). Generally, miRNAs are transcribed as a large miRNA precursor by RNA Pol II, and they mature trough a multistep processing in the nucleus and the cytoplasm (Di Leva et al., 2014). The mature miRNA is incorporated into the RNA-induced silencing complex (RISC) and induces posttranscriptional gene silencing in its target (Bartel, 2009, Fabian and Sonenberg, 2012) Until now, a lot of data from a wide spectrum of cancer has supported the idea that “aberrant miRNA expression is the rule rather than the exception in cancer” (Croce, 2009). They can control several cancer-relevant processes such as proliferation (Hwang and Mendell, 2006) apoptosis (Jovanovic and Hengartner, 2006) migration and invasion (Baranwal and Alahari, 2010). Recent studies also show that miRNAs play a key role in stem cell differentiation (Heinrich and Dimmeler, 2012). They can regulate the formation of cancer stem cells (CSCs) (Peter, 2010, Shimono et al., 2009) and the acquisition of the epithelial–mesenchymal transition (EMT) phenotype (Adam et al., 2009) which are critically associated with drug resistance. MicroRNAs can target up to several hundred mRNAs, which makes them very powerful regulators and an aberrant miRNA expression can disturb a multitude of cell signaling pathways and profoundly influence cancer onset and progression. In the last 10 years hundreds of studies lead to the realization that miRNA profiles can distinguish between normal and cancerous tissue, identify tissues of origin and discriminate different subtypes of a particular cancers or even specific oncogenic abnormalities (Iorio and Croce, 2012). Additionally, recent studies show that miRNA profiling may discriminate between different subgroups of tumors (Caramuta et al., 2010, Li et al., 2010) and predict outcome or response to therapy (Giovannetti et al., 2010, Schetter et al., 2008). Furthermore, miRNAs are important indicators for drug resistance, as the expression of miRNAs in chemoresistant cancer cells often differs from that in their parental chemosensitive cells (Ma et al., 2010). Recent studies found a different expression of circulating miRNAs in the serum of cancer patients, a discovery which has opened a new field in cancer prevention and early detection. Indeed, differentially expressed miRNAs can be detected in patient serum even at an early stage of various cancers (Rabinowits et al., 2009, Taylor and Gercel-Taylor, 2008). These findings have focused attention on these small molecules as potential clinical biomarkers for diagnostic, predictive and prognostic purposes. Finally, current studies moved toward the application of microRNAs in cancer therapy as a new approach to interfere with the molecular mechanism of malignancies (Bader et al., 2011).
Section snippets
MicroRNA biogenesis
MicroRNA (miRNA) genes are evolutionally conserved. Their location is either within the introns or exons of protein-coding genes (about the 70%) or in the intergenic areas (30%). While the expression of the intergenic microRNAs is related to their host gene expression, all intragenic microRNAs have independent transcription units (Rodriguez et al., 2004). MicroRNAs are transcribed, capped and polyadenylated by RNA polymerase II. This process generates a long primary transcript called pri-miRNA (
MicroRNA deregulation in cancer
The first indication of a link between microRNA deregulation and cancer has been uncovered in a study by Croce and colleagues. They found that the miR15a/16-1 cluster is frequently deleted in chronic lymphocytic leukemia (CLL), concluding that these two microRNAs have a tumor suppressor activity (Calin et al., 2002). After this first study a great number of microRNAs have been found deregulated in cancer. Most often, their expression is repressed compared to normal tissues, however there are
MicroRNAs and drug resistance
Chemotherapy, surgery and radiotherapy are valid approaches for cancer treatment. In particular chemotherapy is very often effective in reducing tumor cell growth and to counteract metastatic progression. However, especially in advanced cancer, chemotherapy is often ineffective due to the development of chemoresistance. As a result of drug resistance, tumors often recur more aggressively and gain the ability to metastasize to distant organs. We already described microRNAs as regulators of gene
MicroRNAs as biomarkers
In the last years the literature presented a lot of evidence that microRNAs are involved in practically all kinds of cancers and malignancies. New technologies like microarray analysis and next generation sequencing (NGS) allowed us to extensively study the relation between microRNAs and cancer by examining the whole expression profile of this class of small non-coding RNAs in tumors. In 2005 Volinia et al. used a microarray platform to define the microRNA signature of six human solid tumors.
MicroRNA therapy
In recent years, cancer drug therapy has increased the patient survival and reduced the overall mortality rates. However, the development of new drugs with more target specificity is needed. The therapeutic application of microRNAs in cancer is a new and exciting approach to interfere with the molecular mechanism of malignancies. The first possible application of microRNAs in cancer is based on the reintroduction of a single or multiple mimic microRNAs (non natural double-stranded miRNA-like
Conclusions
Over the last years a great number of different classes of ncRNAs have been discovered and classified according to their function and size (Dogini et al., 2014). MicroRNAs are a class of small non-coding RNAs (sncRNAs) that play an important role in the regulation of a large number of biological processes and diseases, including cancer (Iorio and Croce, 2012). Since the discovery of the relation between miR-15 and miR-16 deletion and CLL, a constantly growing number of studies and publications
Conflict of interest
The authors declare no conflict of interest.
Acknowledgments
This study was supported by NIH grants to (CMC) UO1 CA152758 and RO1 CA151319.
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