Abstract: MicroRNAs are small noncoding RNAs with lengths of 21-22 nucleotides that participate in post-transcriptional control of gene expression. According to recent studies, 2588 microRNAs have been detected and the list is growing. Furthermore, microRNA (miRNA) plays a major role in regulating biological processes and miRNA in relation to many diseases including cancer. The deregulation connection between miRNA and cancer was discovered in 2002. Today, even more information about the main role that miRNA plays in cancer development has been uncovered, however, there is still a long way to go to understand the functions of all the microRNAs in eukaryotes. In this review, briefly explained miRNA biogenesis and discuss the roles that miRNAs play in cancer development. Finally, discussed how miRNAs can be used as biomarkers and as a new therapeutic approach in cancer.
INTRODUCTION
MicroRNAs (miRNAs), small noncoding ribonucleic acids of approximately 21-22 nucleotides in length, are present in the majority of eukaryotic cells where they play an important role in a range of biological processes. MicroRNAs operate by regulating gene expression via binding to a complementary sequence in the target messenger RNA (mRNA). MicroRNAs were first discovered in 1993 in Caenorhabditis elegans1 during a study of the short noncoding RNA family2. Twenty-three years after their discovery, miRNAs were shown to be key regulators of development3. In fact, the miRNA database, updated in 2014, revealed 2588 mature miRNAs in humans and at least 1915 in mice. It has been estimated that miRNAs help to regulate ~60-70% of the human genome4. MicroRNAs have been shown to play a role in several diseases, including some nervous and metabolic disorders and cancer5. A major role has also been reported in cancer stem cell differentiation6. Furthermore, miRNAs can function as indicators of drug resistance, as the expression of miRNAs in chemo resistant cells often differs from that in the parental chemo sensitive cells7. In this review, we discuss the application of microRNAs in cancer therapy and in the treatment of other diseases8.
MicroRNA and biogenesis: The biogenesis of miRNA occurs via a well-characterized conserved mechanism. MicroRNA is intragenic RNA, with its own dedicated transcription factor9. MicroRNAs are transcribed, polyadenylated and capped by RNA polymerase II, producing an extended primary transcript designated pri-miRNA. A method involving the Dorsha/DGCR8 heterodimer then crops the pri-miRNA, producing a transcript of ~70 kb, an miRNA precursor known as pri-miRNA (Fig. 1).
Furthermore, the exportin-5 (XPO5) and Ran-GTP binding the pre-mRNA and also the export of this molecule from the nucleus into the cytoplasm10. The pre-miRNA is known by the RNase III dicer protein and manufacturing a mature miRNA duplex of twenty-two nucleotides. miRNA the double strand binding to the RNA-inducing silencing complex (RICS). RISC is combined of the transcription-responsive RNA-binding (TRBP) and Argounaute2(Ago2)11. It retains the mature strand fragment whereas the complementary strand is removed and degraded12. In as result, the most 3 basic steps of miRNA biogenesis mature are dicing, export and cropping of pri-miRNA.
MicroRNA and cancer: The first study reported in 2002 that the miR15a/16-1 cluster is usually deleted in chronic lymphocytic leukemia (CLL), significantly that these two microRNAs is TSGs13, after this 1st study a large variety of microRNA are found deregulated in cancer14.
| Fig. 1: | Schematic review of miRNA biogenesis and miRNA-RISC activity |
Expression analysis of normal tissue, however, there are also microRNAs which are overexpression in cancer. For instance, the transgenic expression of miR-21 and miR-155 is enough to induce lymphomagenesis in mice15. Furthermore, characterizations of Dicer knockout races have analysis the significance of the miRNA control system as such as in both typical and cancerous cells16. Tumors regularly display reduced levels of developing miRNAs17. Diminished Dicer expression level has been found in the human tumor18. This framework is not without limitation: one miRNA can target multiple cellular pathways and is communicated everywhere throughout the body. There is a possibility of off-target or undesired impact19.
MicroRNA and human cancer database: In reality, it has been utilizing computational expectations and trials, for instance miRNAMap2.0, miRBase, miRGen, miRGator v2.0 and miRecords. Other databases, such as Targetscan, Pictar and TargetMiner, are based on an algorithm intended to foresee microRNA focuses as indicated by a complementary pairing sequence20.
Another database, TarBase, uses confirmed microRNA objectives, even when RNA hybrids are based on hybridization among miRNA and mRNA21. There are additional databases that give data on numerous illnesses, such as PhenomiR 2.0, mir2Disease and MicroCosm22. This review presents many recently revealed internet based tools that are mainly for determining the relationship amongst miRNA and cancer (Table 1).
SomamiR DB 2.0: Circular RNA (CircRNA) and long noncoding RNA (lncRNA) can periodically impart target mRNA to miRNAs. These can frame a contending endogenous RNA network as a community between the cRNA network and cancer23. SomamiRDB 2.0 was produced to perform a search of somatic mutations in miRNAs and ceRNAs (mRNA, CircRNAs and LncRNAs) to help to researchers find a function to search these mutations in human malignancy24.
miRCancer: miRCancer is web based and holds reserve records of miRNA and cancer associations gathered through data processing25. miRCancer has records of >3,764 miRNA tumor relationships from 2,611 distributions, which adds up to 236 miRNA expression profiles from 176 human malignancies. miRCancer is simple and available on the web and the database can be searched via miRNA name, cancer type or a blend of both26.
Relation between specific cancer and miRNA database
HNOCDB: A great aspiration of humans is improving treatment and medical care. For example, oral carcinomas, such as tongue, salivary gland, thyroid, pharyngeal, nasopharyngeal, oropharyngeal and laryngeal cancer are the most typical cancers in the world and curious to treat due to their area27. HNOCDB (http://gyanxet.com/hno.html): The genes were characterized according to the types of cancer and have three main important options for the user," genes", "miRNA " and chromosome association with interesting cancers28.
From the result, HNOCDB is the best database that has good classification of the miRNA, genes and chromosomes involved in head, neck and oral cancer29. Databases focus on a specific kind of malignancy, such as HNOCDB, miREC, the renal cancer gene database, the pancreatic cancer database and the other cancer databases, are valuable to those specialists who need to concentrate the that part of the miRNAs in the growth of biogenesis and evolution. Different databases (CanEvolve, CancerNet, miRCancer, OncomiRdbd, AutomiRDb and ProgmiR) that review the part of miRNAs in various tumors can be used to see the master plan of a specific miRNA in various pathologies30.
MicroRNA as a biomarker: In recent years, the literature reported a large number of evidence on microRNAs being concerned with all types of cancer and maladies31. New invention in molecular biology, such as microarray and next-generation sequencing (NGS), allow us to extensively research the connection between microRNA and cancer by analyzing the whole expression profile of this class-noncoding RNA in tumor tissue or blood32. In 2005, researchers used microarray to define six humans solid cancer33. The resulting profile gain from normal and tumor tissue displays that then prevalent idea that micoRNAs were only downregulation in cancer was wrong. Also, miR-21, miR-17-5p and miR-191 were shown to be overexpressed in some cancer34. A study conducted on 22 completely different growth varieties showed that a microRNA expression profile is ready to classify tumors per tissue of origin with accuracy more than ninetieth microRNAs are shown to even have a job in cancer progression and may well be helpful for the prediction of pathological process outcome in patients35.
Recently, miRNA profile expressions of 82 colorectal carcinoma patients35, discovery that a microRNA profile is ready to discriminate between large intense recurrences to lymph nodes, liver, between colorectal liver and first internal organ neoplasm36. Now used to as a clinical factor, microRNA have analysis in different studies as a biomarker for treatment therapy37,38.
| Table 1: | Web-based tools for miRNAs in human cancer |
| Table 2: | MicroRNA and Human disease |
MicroRNA and Cancer treatment: In recent years, cancer drug therapy has increased the cure rate from malignant tumors and decreased the rate of cancer-related mortality worldwide39. However, novel drugs with improved target specificity are needed. The use of microRNA is a novel and exciting approach to the development of cancer therapeutics, allowing for the targeting of specific molecular mechanisms or cellular processes related to malignancies40. Advances in in silico tools have aided the design and manipulation of microRNAs and their target genes. Furthermore, the use of siRNA allows for the inhibition of multiple targets41. Recent progress in the development of efficient carriers for transferring small RNAs intracellularly, such as nanoparticles and viral systems, has aided the application of microRNA technology42. In addition, mRNA antagonists can be used as therapeutic tools to inhibit oncogenic miRNA43. Anti-miRs are single-stranded RNA molecules of 21-23 nucleotides in length that bind to target microRNAs and inhibit their function44. The adaptation of tumor cells to respond to therapeutically-evoked pathway changes45 is one of the challenges faced when delivering microRNAs in vivo. One of the most effective approaches to overcome such problems is the use of nanoparticles that are able to deliver small interfering RNAs (siRNAs) and microRNAs in a neoplasm-specific manner46.
SNPs in miRNA and role in human disease: Single nucleotide polymorphisms (SNPs) happen within 1% or more of the population47. There are around 8-10 million SNPs in the human genome and happen once in 300bp in both the coding and non-coding regions of the gene48. Nowadays, more attention has been paid by researchers to the SNPs in the non-coding region. In general, we call the mregulatory SNPs (rSNPs) because they impact on transcriptional regulation or post-transcriptional gene expression. rSNPs control and change function in cells at the different level of gene regulation. For instance, they can affect the transcription factor49 of gene splicing50. They can likewise influence the half-existence of messenger RNA (mRNA), which can result in diminished protein levels through mRNA-microRNA (miRNA) cooperation. SNPs in miRNA target sites within the 30-UTR of mRNAs are observed as poly-miRTSs51.Given that there are roughly 19000-20000 genes within the human genome, this implies that the bulk of the genes might be controlled by miRNAs52. Most of miRNA SNPs are link to with maladies53. Their biological function is hard to elicit given that adjustment in any miRNA can have vast genome-wide impacts, as can interaction with hundreds of different mRNAs54. Furthermore, new research has demonstrated how miRNA work in targeted genome editing with the in vitro method to prepare novel instruments for complicated confirmation of miRNA SNP consequence55.
It was discussed that how microRNA play a critical role in a large range of development processes including metabolism cells, apoptosis and progress timing56. Other roles of microRNA in the body include neuronal gene expression, stem cell division and muscle differentiation57. MicroRNA as a major source in the development of cancer cells is still very much unknown58. According to the latest research, microRNA can lead to a malignant tumor within the cell59. In addition, there is some microRNA relevant to the human disease in Table 2.
CONCLUSION
In recent years, microRNAs have been studied as promising potential screening and prognostic biomarkers for cancer. MicroRNA profiling in a wide range of cancer types could provide insight that may be valuable in the development of effective, rapid and economical diagnostic assays for cancer and drug resistance, which may reduce the duration of hospital stays and treatment costs. Such advances represent new frontiers in microRNA-based cancer therapeutic strategies but the challenge of tumor-specific treatment remains an obstacle to be overcome.
SIGNIFICANCE STATEMENT
This study will help the researcher to uncover the critical areas of miRNA biology of cancer that previous generations of researchers could not explore. Thus a new theory on the answer to the obstacle relates to the microRNA and cancer such as nanocarrier for transfer microRNA, there are some of the genetic disorders that researchers can gain to it.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the colleagues from the departments of surgery and Cancer institute at Imam Khomeini complex Hospital, Tehran, Iran and also the colleagues in the Division of Tumor board for their help in gathering and preparing the manuscript.