Recentadvances in sequencing technologies have revealed new secrets of the genome. Interestingly, it is now evident that only2% of human genome encodesproteins and 98% of it is actively transcribed into RNA molecules that losttheir protein coding capacity and called non coding RNAs. MiRNAs as the most widely described non-coding RNAsare a class of smallmolecules with 19-24 nucleotides in length that play important roles in manybiological pathways. Lin-4 was the first miRNA which was identified by victorAmbros and colleagues in C. elegance in 1993 and since then miRNAs have beenexamined in many studies considerably. According to the miRBase (http://www.mirbase.org),a miRNA database, until now, more than 2500 miRNAs in humans and approximately1915 in mice have been recognized and the list is growing.
The vast majority ofmiRNA genes are located within the introns or exons of protein codinggenes(about 70%) and small part them are in the intergenic areas(30%). miRNAs have critical roles inpost transcriptional regulation of gene expression and based on complementarysequence between them and 3-untranslated region (3’UTR) of the target messengerRNA (mRNA), downregulate the gene expression by mRNA cleavage or translationalrepression (Bartel,2009). Thebiogenesis of these short single strand RNAs occurs by a well characterizedmechanisms which is depicted in figure 1.
Firstly, in the nucleus, miRNA genesare transcribed by RNA polymerase II (pol II) to form along primary transcript calledprimary miRNA (pri-miRNA). Then, pri-miRNA is processed byDrosha complex in the nucleus, producing atranscript about 70 nucleotides, called precursor miRNA (pre-miRNA). At thispoint, protein exportin 5 transfers the pre-miRNA from nucleus to the cytoplasmwhere it converts to a mature miRNA duplex of about 20-22 nucleotides by Dicer complex.After strand separation, the passenger strand is removed and degraded but theother strand is incorporated into RNA-induced silencing complex (RISC) andguide it to the target mRNAs for regulation of gene expression at posttranscriptional level via inhibition of translation or degradation of targettranscripts. Computational analyses show that each miRNA may be able to target more than 100 differenttranscripts and adjust the expression of them. Indeed, over 60% of humanprotein-coding genes are regulated by miRNAs, implicating that they can act askey regulators of many biological events including proliferation, development,differentiation, apoptosis and metabolism. Therefore, it is not surprising thattheir aberrant expression contributes tovarious diseases such as cancer.3.
MicroRNA and cancerThe first evidence for the involvement ofmiRNAs in cancer was reported by Calin and colleagues in 2002, who discovered acluster of two microRNAs, miR-15 and miR-16, at critical region 13q14,frequently deleted in chronic lymphocytic leukemia (CLL). Since then, a greatnumber of dysregulated miRNAs have been discovered in many cancers. MiRNAs canact as oncogene or tumor suppressor which respectively up regulation and downregulation of them can be related to the initiation and progression ofdifferent malignancies by affecting several cancer related process including proliferation,apoptosis, invasion and angiogenesis. The most dysregulated miRNAs in cancerhas been summarized in Table1.Although the aberrant expression of miRNAs incancer is a proven fact, the exact causes of its have not yet been fully determined.
For this reason, manyresearchers around the world have focused their attention on uncovering ofthese mechanisms. Until now, several possible causes have been presented.one ofthem is chromosomal abnormalities, like miR-15 and miR-16, as previouslymentioned are located in a frequently deleted genomic region in CLL. Inaddition to structural genetic alteration, miRNAs expression can be also affected by altered activity of the enzymes involved inthe biogenesis of microRNAs,like Drosha and Dicer. For instance, down regulation of Drosha and Dicercomplex has been reported in 39% of ovarian cancer patients. Indeed, it seemsthat decreased expression of level of Drosha and Dicer complex promotescellular transformation and tumourgenesis in vivo.
MicroRNA expression can bealso modulated by other miRNAs. For example, mouse miR-709 located in the nucleus preventing from pri-miR-15a/16-1processing into pre-miR-15a/16-1 by directly binding torecognition site on pri-miR-15a/16-1. Epigenetic changes are another causes of deregulatedmicroRNA expression in cancer which is well reported in various literatures.For example, epigenetic repression of tumor suppressor miR-129-2in endometrialcancer causes the over expression of the SOX4, an oncogene belonging to theSRY-related high mobility group box family.
Notably, miRNAs can also regulatethe expression of enzymes responsible for epigenetic controlwhich is complicated the scenario connecting microRNAsand epigenetics. For instance, it has been determined that miR-143 directlytargets DNA methyltranferase 3A DNMT3A in colorectal cancer. Eventually,deregulated miRNA expression in cancer can be created as a result of alteredtranscription factor activity.
For example, miR-34a, as commonly deleted miRNAin human cancers, is directly transactivated by p53. Furthermore, as expected insignificant number of ovarian cancer patients with p53 mutation, due to the lossof p53 function decreased expression of the miR-34 family was observed.Over the recent years, the extensive miRNAprofiling studies have demonstrated that there are significantly differencesbetween miRNA profiles in cancer cells compared with those in normal cells,suggesting that they have great potential utility as clinical biomarkers andcan also significantly help to the early detection of cancer. For example, inductal adenocarcinoma prior to any phenotypic changes in ducts overexpressionof miR-205 and miR-21 has been reported, implicating that aberrant miRNAexpression is an early event in the development of cancer that can derive abenefit for early diagnosis of cancers.