Introduction binding to corresponding mRNA strands, and this

Introduction 1-Noncoding RNAs Only 1%of the DNA code from the human genome for genes that function in protein synthesis in the cell. The remaining 99% of the deoxyribonucleic acid (DNA) was initially recognized to be junk. Junk DNA knows non-codon DNA is now recognized that the majority of the genome may have biochemical functions, representing DNA transcription, RNA regulatory transcription and protein translation, noncoding ribonucleic acid (RNA). Many subcategories of noncoding RNAs exist, in particular, long noncoding RNAs (lncRNA) , medium non-codon RNA, small noncoding RNAs miRNA, siRNA and piRNA, initiation RNAs transcription , promoter-upstream transcripts, and promoter-associated small RNAs all of which appear to be involved in regulating transcription in cell 1 . Between these non-coding RNAs, exist microRNAs (miRNAs), distinctly is different type have attracted a large deal of global attention.

Figure1. RNA universe classification is based coding and non-coding RNA miRNAs DiscoverymiRNA the first discovery was in 1993 call small transcripts produced by the lin-4 gene in Caenorhabditis elegans 2. These transcripts were found to be very small to mRNAs, yet had corresponding sequences to another gene, lin-14, which appeared to suggest inhibition of the translation 2. In the next decade, the mRNA area expanded quickly and the significance of miRNA in cellular regulation was revealed Normally, miRNAs are viewed as key regulators of the cell through their capability to inhibit translation by binding to corresponding mRNA strands, and this is process marks their targets for degradation or inhibition translate protein, the mechanism of which is shown in our previous paper 3.

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In 2002 few than a decade after the initial discovery, the first role of microRNAs in cancer was discovered initially, miR-15 and miR-16 were shown to be deregulated in chronic lymphocytic leukemia, betoken discovery of tumor suppressed miRNAs 4. Three years later, the first dubbed ‘oncomiR’ was reported when a cistron /cluster located at the 13q21 locus was found to contain multiple open reading frames encoding small transcripts 5. This locus, usually amplified in different lymphomas, was found to contain the miR-17-92 cluster which performed at least seven oncogenic or tumor suppressive miRNAs 6. After the first identification of miRNA and its cancer Connection, several cancers were examined for aberrant miRNA expression and in later year lung and colon carcinomas, as well as multiple lymphomas, were found to exhibit upregulated and downregulated miRNAs 7, 8. The dysregulation of miRNAs is shown to lead toward the onset and progress of Oncogenesis. In special, oncogenic miRNAs, when overexpressed function as oncogenes by downregulating tumor suppressors and another similar regulatory gene 9.

In breast cancer and liver cancer, pancreas cancer and lung cancer some of the first oncomiRs dysregulated were miR-21, miR-155 and miR-125b 10. During aberrant expression, oncogenic miRNAs can encourage tumor growth by allowing cell cycle progress, inhibiting apoptosis pathways, stimulating growth and proliferation and encourage invasion and metastasis 11. 2- MicroRNAs: biogenesis and mechanisms of action2-1 biogenesis50% of miRNA-coding genes remain in the intergenic area and are can be regulated by their own promoters, approximately 40% of miRNA genes are located in introns and the final 10% of miRNA are found in exon terminals12, 13. As the result, the expression of 50% of the miRNA genes relies on the regulation of their host gene, so they may be included in the control of genetic networks correlated to the expected function of host gene product 14. An interesting characteristic is that many miRNAs genes are consistent within clusters, with an intergenic distance ranging from 0.

1 to 50 kb, and thus exhibit a similar expression 15. as well as, often miRNAs within clusters are, but not always, related to each other, while miRNAs from the same group are occasionally clustered 16.transcribed miRNA into primary-miRNA (pri-miRNA) by RNA polymerase II but can as well be transcribed by RNA polymerase III17.

a large stem-loop structure with a 5? cap and a poly (A) tail of pri-miRNA is recognized by the ribonuclease Drosha, the RNA-binding protein DGCR8 and another auxiliary factor 18.after that, the pri-miRNA is cleaved by Drosha (RNase III endonuclease or RNase II endonuclease )producing a 50-60 nt stem-loop intermediate recognized as pre-miRNA19,20. Exportin-5 and Ran- GTP activity on transported pre-miRNA from the nucleus to the cytoplasm 21. Once there, by Dicer RNase III endonuclease that cleaves loop and the terminal base pairs leaving an imperfectly matching duplex of the pre-miRNA. At this stage, just one strand is ultimately joined into the RNA-induced silencing complex (RISC), the “guide” strand, while the other strand called “the passenger” (also called the miRNA* strand) degenerates. The criteria still to determining which of the two strands is loaded into the RISC need to be explained but it seems that, in most of the cases, it is the one whose 5? end is less tightly paired 22.

In addition to miRNA biogenesis, Drosha/DGCR8 are processed from the intron of the protein-coding gene by the pre-mRNA splicing machinery is also the independent pathway of miRNAs 23.miRNA expression called miRtrons is connected to the expression of the host gene because they lie in splice site junctions24. miRtrons are processed by Dicer after exported to the cytoplasm.Figure3.

Key Steps in miRNA Biogenesis2-2-miRNA actionThe mechanism of inhibition or degradation by miRNAs is interactions between miRNAs and mRNAs it complex network interactions. In fact, multiple genes inhibitions by one single miRNA at the same time, multiple miRNA can be the target of one gene 25. These interactions are important goodto the modality of hybridization between the sequence of miRNA and 3? untranslated region (UTR) a specific sequence of the target mRNA. target mRNA has a nucleotide sequence is engaged in miRNA binding is named the miRNA Recognition Element (MRE) or “seed region”26.

The varies composition of this seed region but always includes a sequence with conserved Watson-Crick pairing (i.e. the hydrogen bonds that pairs guanine-cytosine and adenine-thymine) to the 5? region on nucleotides 2–7 of the miRNA centered27.

Seed regions contain Several types and that depending on the length and structure of the sequence involved in miRNA: mRNA binding, resulting in different inhibition and affinities properties. sites with a 6–8-nucleotide match These include canonical between miRNA and mRNA and the 3? end of the miRNA non-canonical sites that include additional pairing. Additional factors have been shown to affect miRNA seed efficiency like AU-rich sites, it is more effective 28. A post-transcriptional regulation of gene expression is the start point of miRNA binding to its target mRNA in the cytoplasm, often by translational inhibition or mRNA degradation 29. Indeed, miRNA-RISC-mediated gene inhibition has been exhibited to arise from three putative mechanisms site-specific break, translational inhibition and enhanced mRNA degeneration 30.

Figure 2-2 mechanisms miRNA in inhibition mRNA in the cell 3-The role of microRNAs in cancer. 1 Temo Barwari, MD, Abhishek Joshi, BA, BMBCH,et al .microRNAs cardiovascular disease. J Am Coll Cardiol 2016;68:2577–84. 2Lee RC, Feinbaum RL, Ambros V. The C.

elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993;75(5):843e54.3 Eastlack SC, Alahari SK. MicroRNA and breast cancer: understanding pathogenesis, improving management.

Non-Coding RNA 2015;1(1):17e43.4 Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci 2002;99(24):15524e9.

5 He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature 2005;435(7043):828e33.6 Michael MZ, O’Connor SM, van Holst Pellekaan NG, Young GP, James RJ.

Reduced accumulation of specific micro-mRNAs in colorectal neoplasia. Mol Cancer Res 2003;1(12): 882e91.7 Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, et al. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival.

Cancer Res 2004;64(11):3753e6.8 Metzler M, Wilda M, Busch K, Viehmann S, Borkhardt A. Highexpression of precursor microRNA-155/BIC RNA in children withBurkitt lymphoma.Genes ChromosomesCancer 2004;39(2):167e9.

9 Shenouda SK, Alahari SK. MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev 2009; 28(3e4):369e78.10 Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer.

Cancer Res 2005;65 (16):7065e70.11 Baranwal S, Alahari SK. miRNA control of tumor cell invasion and metastasis. Int J Cancer 2010;126(6):1283e90.12-Lagos-Quintana, M., Rauhut, R.

, Lendeckel,et al. Identification of novelgenes coding for small expressed RNAs. Science 2001; (80-) 294, 853–858.13- Skog, J.

, Würdinger, T., van Rijn, S., et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers.

Nature Cell Biology 2008; 10, 1470–1476.14-O’Carroll, D., & Schaefer, A.

General principals of miRNA biogenesis and regulation in the brain. Neuropsycho pharmacology 2013; 38, 39–54.15-Baskerville, S., & Bartel, D.

P. Microarray profiling of microRNAs reveals frequentcoexpression with neighboring miRNAs and host genes. RNA 2005; 11, 241–247.

16-Lagos-Quintana, M., Rauhut, R., Lendeckel,et al . Identification of novel genes coding for small expressed RNAs.

Science 2001 (80-) 294, 853–858.17-Lee, Y., Kim, M.

, Han, J. et al. MicroRNA genes are transcribed by RNA polymerase II. The EMBO Journal 2004; 23, 4051-4060.18-Cai, X., Hagedorn, et al .

Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA 2004; 10, 1957–1966.19- Denli, A.M.

, Tops, et al .processing of primary microRNAs by the microprocessor complex. Nature 2004; 432, 231–235.20- Y. Lee, C. Ahn, J.

Han, et al. RNase III Drosha initiates microRNA processing Y. RNase III Drosha initiates microRNA processing.

Nature, (2003);425 pp. 415-41921- Lund, Guttinger, Calado, et al. Nuclear export of microRNA precursors. Science, 2004;303 (5654):95-8.22- Khvorova, Reynolds, & Jayasena.

Functional siRNAs and miRNAs exhibit strand bias. cell 2003 ;115(2):209-16.23- Grimson, A., Farh, K.

K., Johnston,W. K.

, et al. MicroRNA targeting specificity in mammals: Determinants beyond seed pairing.Molecular Cell. 2007; 27, 91–105.24- Issler, O.

, Haramati, S., Paul, E. D.

, et al. MicroRNA135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron 2014; 83, 344–360.25-Peter,M. E.

Targeting ofmRNAs by multiple miRNAs: The next step. Oncogene . 2010;29,2161–2164.26- Shukla, Singh, & Barik.

MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions.mol cell pharmaocol.  2011;3(3):83-92.30- Bartel, D. P.

MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell ,2004: 116,281–297.27-Bartel, D. P. MicroRNAs: Target recognition and regulatory functions.

Cell , 2009; 136,215– 233.28- Pasquinelli. NON-CODING RNA MicroRNAs and their targets:recognition, regulation and an emerging reciprocal relationship. Nature review genetics.2012: 13(4):271-82.

29-Jackson, R. J., & Standart, N. How do microRNAs regulate Gene expression?Science’s STKE.



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