miRNAs & Cancer
miRNAs (also known as miRs) are a family of small ncRNAs (19–25 nucleotides in length) that regulate gene expression by sequence-selective targeting of mRNAs, leading to degradation or blockade of mRNA at the post-transcriptional level, depending on the degree of complementarity between miRNAs and the target mRNA sequence.
For the majority of miRNAs, the primary transcripts are generated in the nucleus. Following transcription, the pri-miRNA is processed by DROSHA and its binding partner DGCR8 (also known as Pasha), creating a pre-miRNA. The pre-miRNAs are exported to the cytoplasm by the nuclear export protein XPO5, where they are further processed by DICER, leading to the production of mature approximately 22 nucleotide double-stranded molecules. The mature miRNA enters the miRISC complex where it is further processed, leaving a single-stranded functional miRNA. This single-stranded miRNA then induces post-transcriptional gene silencing by guiding the miRISC complex to target mRNAs. Target recognition occurs mainly by incomplete base pairing complementarity between the miRNA and the target mRNA, resulting in mismatches that, in turn, lead to target gene silencing, which can occur via translational repression and/or mRNA degradation (Figure 2).
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Figure 2.
miRNA biogenesis and processing mechanism.
miRNA expression is dynamic, so may be altered within the same cell. This variability makes miRNAs potent modulators of cellular behavior, since several miRNAs can target the same gene and one single miRNA can target multiple genes. Hence, miRNAs have been identified as key regulators in many biological processes including cell development, differentiation, apoptosis and proliferation. miRNAs deregulation can modulate the renal cell microenvironment, which can impact on cancer development. We previously observed that slight differences in microenvironment, owing to functional SNPs, can be associated with RCC development.
As a single miRNA may target up to several hundred mRNAs, aberrant miRNA expression may affect a multitude of transcripts and profoundly influence cancer-related signaling pathways. Many miRNAs have been identified to act as oncogenes, tumor suppressors or even modulators of cancer stem cells and metastasis formation. OncomiRs are known to downregulate tumor suppressor genes, and have been reported to be overexpressed in multiple miRNA expression-profiling studies. On the other hand, tumor suppressor miRNAs are responsible for downregulating oncogenes, and are mostly underexpressed in cancer. Duns and coworkers reported that the miR-200 family, a family of tumor suppressor miRNAs known to be implicated in the epithelial-to-mesenchymal transition process, are deregulated in clear cell (ccRCC).
miRNAs represent attractive drug targets since they regulate the expression of several cellular proteins and are differentially expressed in malignant cells when compared to normal cells.