Exploring miRNA based approaches in cancer diagnostics and therapeutics
Introduction
Uncontrolled proliferation of damaged cells, as a result of deregulation of genes involved in the cell cycle machinery and apoptosis, leads to tumor formation (Vecchione and Croce, 2010). Accounting for approximately 3% of the human genome, miRNAs are 22 nucleotides long, single stranded RNAs found in both plants and animals (Setoyama et al., 2011). The biogenesis of miRNAs is well defined in literature. Briefly, a stem-loop structure of pri-miRNA (primary miRNA) of about 1 Kb in size, transcribed by RNA polymerase II undergoes a two step maturation phase. Initially, the RNase III enzyme Drosha and ds-RNA binding endonuclease Pasha (DGCR8) process it into a 70 nucleotides pre-miRNA by cleaving both the strands and generating a stem loop structure (Krishnan et al., 2011, Zhiguo et al., 2008). The pre-miRNA is then transported to the cytoplasm with the help of a RAN GTP-dependent transporter exportin 5 for further processing by RNA III enzyme Dicer and ds-RNA binding protein TRBP (Transactivating Response RNA-Binding Protein), hence generating a 22 nucleotides miRNA: miRNA* duplex. The duplex is incorporated to the RISC (RNA induced silencing complex) complex wherein the mature miRNA strand is retained and the miRNA* fragment is degraded, guiding the RISC to the target mRNA molecule for gene regulation, which is a sequence complementarity dependent process. Perfect complementarity of the “seed region” with target mRNA results into its RISC associated degradation while imperfect matching leads to translation repression as 5′ end of miRNA binds to the 3′ UTR (untranslated region) of the target gene (Zhang et al., 2007, Xiangyang et al., 2008, Stefanie et al., 2008) [Fig. 1].
Miss-expression or mutation of factors involved in miRNA biogenesis could result into alterations in miRNA processing, stability, and targeting, hence causing serious ailments including cancers. The potential role of miRNAs in cancer is suggested owing to their involvement in the regulation of cell proliferation and apoptosis by controlling the expression of tumor suppressor genes and oncogenes. Additionally supporting this, about 50% of miRNAs are found to be located at “fragile sites” in the genome, which are the sites mostly amplified or deleted in cancer. Microarray, bead-based flow cytometry, sequencing and RT-PCR (Real Time-polymerase chain reaction) are some of the techniques used for analyzing the differential expression of genes in normal and cancerous cells, to elucidate the exact role of miRNAs in carcinogenesis (Monya, 2010). It has been reported that miR-10b, miR-125b and miR-145 are down-regulated while miR-21 and miR-155 are up-regulated in cancer development, hence playing roles as tumor suppressors and oncogenes, respectively (Thalia et al., 2011). Moreover, rearrangements in the gene regions containing miRNAs have been identified indicating their altered expression levels in the neoplastic cells. Their differential expression profiling thus gives information both on the differentiation state and developmental lineage of tumor, thereby paving way for cancer diagnosis and therapy (Niamh et al., 2009).
Section snippets
Role of miRNAs in cancer development
Studies suggest that miRNAs are majorly involved in the onset and progression of cancer. In lung cancer, the expression of dicer is found to be down-regulated, further decreasing the post-operative survival rate as a result of truncated miRNA maturation process (Ruan et al., 2009). Knock down studies with DICER, DGCR8 and TRBP2 genes shows enhanced tumor formation while re-introduction of these genes cause reduction in tumor growth. Genes from other pathways such as LIN28A block processing of
miRNAs in cancer diagnostics
Cancer, a major cause of mortality worldwide, requires better techniques and treatments for which miRNAs may prove to be incredibly beneficial. Many cancer biomarkers are available for diagnostics; however, they fail to delineate benign and malignant tumors and other benign diseases such as cirrhosis, inflammatory bowel disorder, due to their elevation in these ailments. Some of the commonly used markers are CEA (carcinoembryonic antigen) for colon cancer, AFP (alpha-fetoprotein), an associated
miRNA delivery systems in cancer therapeutics
Owing to the function of miRNAs to be used as tumor suppressors and oncomers, they have a great potential to target the pathways involved in cancer development and metastasis. In cancer therapeutics, miRNAs can be used for degrading the anti-apoptotic genes or can be silenced to up-regulate the tumor suppressor genes. For example the restoration of miR-34 inhibited tumor formation while antagonizing miR-21 using anti-sense oligonucleotides causes pro-apoptotic response. The anti-sense
Circulating miRNAs in therapeutics
Through facilitation of cell–cell communication, circulating miRNAs are suggested to serve as potential therapeutic tools. Based upon over-expression or knocking down of these small molecules, several progressive researches are currently going on for employing them in cancer therapeutics (Zhang et al., 2013). The treatment of colorectal cancer by targeting miR-135b which is abnormally up-regulated in diseased state, causing evasion of apoptosis by down-regulating TGFβR2 (Transforming Growth
Recent patented research on miRNAs
Oncomirs, emerging as novel biomarkers for diagnosis, prognosis and treatment of cancer by employing molecular biology techniques are being extensively patented worldwide, which corresponds to a great research being done in this field. The patenting era for miRNAs began in early 2000s and achieved a peak after 2008, showing the intense research being conducted in this field. Amongst the United States (US), Europe (EP) and WIPO patents, US leads in the number of patented applications followed by
Future prospectives in cancer therapeutics
Cancer being a very complex and multi-factorial disease leaves us with many unexplored questions. Curing cancer to its root requires intensive treatment, but still complications develop owing to the side effects of the therapy due to deficient interruption of multi-signaling oncogenic pathways and drug-induced adverse effects. Therefore, new treatment strategies are required to be developed to improve the clinical outcome and quality of life of patients. Employment of miRNAs for targeting the
Conclusions
miRNAs, an emerging class of gene regulators, are involved in many physiological and pathological processes, including cancer. The characterization of deregulated miRNAs in cellular transformation, benign and malignant states, progression of cancer and as a regulator of multiple biological pathways has immense implications and represents a powerful therapeutic strategy in cancer.
Conflict of interest
Authors declare that they have no conflict of interest.
Acknowledgements
This work was supported by a research grant awarded to Dr. Vibha Rani by the Department of Biotechnology (DBT), Government of India (BT/PR3642/AGR/36/709/2011). We acknowledge Department of Biotechnology, Government of India and Jaypee Institute of Information Technology, deemed to be University for providing the funds and infrastructural support.
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