Role of miRNA in liver cancer(HCC)MicroRNAs (miRNAs), discovered byAmbros and colleagues in 1993,iare small noncoding RNAs, 18–24 nucleotides in length, that regulate geneexpression by binding to mRNAs to interfere with the process of translation.
iiGenes that encode miRNAs are transcribed from DNA to a primary transcript(pri-miRNAs), which is processed into a short precursor (pre-miRNA) and thenexported into the cytoplasm where it is further processed into a mature, singlestranded miRNAiii.Most miRNAs are transcribed from intergenic regions by RNApolymerase II. The primary transcripts are precursor molecules (pri-miRNA) thatare processed by two ribonucleases—Drosha in the nucleus and Dicer in thecytoplasm—into mature miRNAs.MiRNAs are endogenous and potentially can regulate every aspect ofcellular activity, including development and proliferation, differentiation,metabolism, viral infection, epigenetic modulation, apoptotic cell death, andtumor genesis. Recent studies provide evidence that miRNAs are abundant in theliver and affect a diverse spectrum of liver functions.ivDifferentclasses of miRNAs can play oncogenic as well as tumor-suppressing roles; thesame group of miRNAs can exhibit oncogenic activity in one tissue type but actas a tumor suppressor in anothervmiRNAs potently influencecellular behavior through the regulation of extensive gene expression networksvivii.
It has been demonstrated thatmost tumors are characterized by globally diminished miRNA expressionviii.MicroRNAs, small noncoding RNAsthat regulate the translation of many genes, are excellent biomarkers forcancer diagnosis and prognosisixChronic infections with eitherHBV or HCV increase the relative risk of liver cancer greatly. These chronicviral infections are present in more than 70% of HCC cases, and iatrogenicinterventions against these viruses significantly reduce the risk of HCCdevelopment.xMethods of Cancer diagnosis:Biological samples such as blood,serum, stool, pancreatic juice or urine, as well as both DNA and RNA, have beenanalyzed for tumor-specific changes.
Additionally genomic DNA alterations,circulating viral DNA or RNA, various mutations such as KRAS, p16 and/or APC either in serum, blood orcirculating cancer cells in blood samples have been evaluated to allow theearly diagnosis of cancer patients. Recently, epigenetic changes such as genemethylation in biological samples from cancer patients have also been analysed.In addition, serum levels of certain proteins involved in tumour biology suchas cathepsin B, E-cadherin, hepatocyte growth factor, interleukins, and othercytokines and hormones have been measured in the serum of cancer patients. However, none of these analysis methods hasyet shown adequate sensitivities and specificities to facilitate the detectionof cancer in its early stagesximiRNA in Cancer Diagnosis: MicroRNAs (miRNAs), discovered byAmbros and colleagues in 1993,xii1are small noncoding RNAs, 18–24 nucleotides in length, that regulate geneexpression by binding to mRNAs to interfere with the process of translation.
xiii2Genes that encode miRNAs are transcribed from DNA to a primary transcript(pri-miRNAs), which is processed into a short precursor (pre-miRNA) and thenexported into the cytoplasm where it is further processed into a mature, singlestranded miRNAxiv.Most miRNAs are transcribed from intergenic regions by RNApolymerase II. The primary transcripts are precursor molecules (pri-miRNA), arecapped, polyadenylated and are usually several thousand bases in lengthxv, that are processed by two ribonucleases—Drosha in the nucleusand Dicer in the cytoplasm—into mature miRNAsxvi. Dicer is involved in formation of a transient 22 ntmature double stranded (ds) miRNA (miRNA duplex). Dicer initiates the formationof the RNA-induced silencing complex (RISC), which is responsible for genesilencing.xviimiRNAs potently influencecellular behavior through the regulation of extensive gene expression networksxviiixixhencethey potentially regulate every aspect of cellular activity, includingdevelopment and proliferation, differentiation, metabolism, viral infection,epigenetic modulation, apoptotic cell death, and tumor genesis.
xxIt has been demonstrated thatmost tumors are characterized by globally diminished miRNA expressionxxi.Different classes of miRNAs can play oncogenic as well astumor-suppressing roles; the same group of miRNAs can exhibit oncogenicactivity in one tissue type but act as a tumor suppressor in anotherxxiiMicroRNAs, small noncoding RNAs that regulate thetranslation of many genes, are excellent biomarkers for cancer diagnosis andprognosisxxiii.Due to advances in oncology, most cancers are diagnosed in advanced stages,leading to poor outcomes.Several aspects of miRNAsincluding their intricate nature of interaction with multiple targets andmultiple pathways make them extremely useful potential agents for clinicaldiagnostics.
The study of miRNA SNPs andmiRNA-binding site SNPs as biomarkers of cancer risk is another way in whichmiRNAs may open up new avenues, allowing early cancer detection. MicroRNA can be used in fivedifferent ways for the diagnosis of cancer:1. Onecan use the micro-RNA for the detection of cancer at very earlier stages; thisis done by using blood out of the patient’s body.
Profiling this blood or usingtumor derived exosomal miRNAs this gives you the benefit of avoiding the otherinvasive methods.2. Theycan also be used in the prediction of cancer predisposition, this is done bytwo different ways which includes; studying the phenomenon of SNPs (abbreviatedas Single Nucleotide Polymorphism) in the gene of miRNA, study the binding siteof miRNA in mRNA.3. MiRNAcan also be used in determination of subtypes of one cancer hence it is used todistinguish between various subtypes of cancer.
In this method we use suchmiRNA that gives differential expression in different types of cancer.4. miRNAcan be used to differentiate cancerous cells from the normal ones, miR-151 is located in a site(8q24.3) that is frequently amplified in HCC.Indeed, miR-151 expression iscorrelated with intrahepatic metastasis of HCC and increases HCC cell migrationand invasion by directly targeting RhoGDIAxxiv miR-122One of the most abundant miRNAsin the liver is miR-122a. It is expressed in normal hepatocytes but isdownregulated in up to 70% of human HCCs. miR-122 loss was also associated withhigh proliferation and low apoptotic featuresxxvMiR-122 is described as aliver-specific miRNA. The expression of miR-122 can be used as a marker ofliver development and it undergoes liver-specific expression during embryonicdevelopment.
A role for miR-122 in hepatocarcinogenesis is suggested by thedifferential expression of miR-122a in HCC versus non-tumor cirrhotic hepatictissue, and by the studies by Kutay et al of miRNA expression in murine HCC. Inthese studies, miR-122a was decreased by 50% in patients of HHC.xxvi Cyclin G1 promotes cell cycleprogression and it may be associated with genomic instability. In HCC cells, aninverse correlation has been observed between miR122a and cyclin G1, which is avalidated target of this miRNA. In experimental hepatocarcinogenesis, loss ofcyclin G1 is associated with a significantly lower tumor incidence aftercarcinogenic challenges. Thus, deregulated expression of cyclin G1, in responseto altered miR122a expression, could contribute to the pathogenesis of livercancer.xxviiCAT-1 is a carrier proteinrequired in the regenerating liver for the transport of cationic amino acidsand polyamines in the late G1 phase, a process that is essential for livercells to enter mitosis.Given these data, modulation of expression of CAT-1 maybe another mechanism through which this miRNA regulates cell cycle in normaland transformed hepatocytesxxviii studies have shown theinvolvement of miRNAs in the regulation of HCV infection.
MiR-122 is firstidentified liver-specific cellular miRNA, which has been shown to enhance thereplication of HCV by targeting the viral 5′ non-coding region48 . It appearsthat HCV replication is associated with an increase in expression ofcholesterol biosynthesis genes that are regulated by miR-122 and hence isconsidered as a potential target for antiviral intervention49 miR26, and miR-223 miR26:Numerous tumors and normaltissues exhibit different expression of miR-26 during growth, development andtumorigenesis and miR-26 may participate in various biological processesthrough imperfect sequence complementarity binding between seed region and 3?UTRof target mRNA. miR-26 may repress the target gene translation and decreaseexpression levels of target gene-coding protein.t has been observed thatexpression of miR-26 is disordered in many tumors and that it has specificfunctions in different tumors.xxixKota etal reported that the expression of miR-26 was down-regulated inhepatocellular carcinoma (HCC) cells and that overexpression of miR-26a inliver cancer cells in vitro inducedan increase in cells of G1 stage as well as a decrease in cells of the S stage,indicating that miR-26a induced a G1 arrest.Systemic administration of thismiRNA to a mouse model of HCC using adeno-associated virus resulted in theinhibition of cancer cell growth and proliferation, and increasedtumor-specific apoptosis. This process indicated that miR-26a was atumor-suppressor miRNAxxx.Expression of miR-26 wasdown-regulated in tumors compared with paired non-cancerous tissues, indicatingthat the sexpression of miR-26 was associated with HCC.
. Moreover, tumors witha reduced miR-26 expression exhibited a distinct transcriptomic pattern andactivated the signaling pathways between nuclear factor ?B and interleukin-6,which may play a role in tumor development according to gene networksinformation. Patients with a lower miR-26 expression in HCC had a shortersurvival but a more favorable response to interferon therapy than those with ahigher miR-26 expression in HCC, indicating that miR-26 was associated withpost-operative survivalxxxiis postulated that about 1%-5% ofgenes in ani-mals encode miRNAs, while 10%-30% of protein-coding genes are predicted miRNAtargets7,8xxxii The importance of miRNAs in theliver immune system is highlighted by the fact that mice lacking Dicer 1function in the liver were unable to produce mature miRNA and showedprogressive hepatocyte damage, apoptosis, and portal inflammationxxxiii China alone accounts for morethan 50% of HCC incidence in the world.884 miRNAs were differentiallyexpressed in HCC versus nontumorous liver tissues, and only miR-125b expressionwas associated with patients’ survival.
10expression of miR-125bwas suppressed in about 70% ofprimary HCCs and was highly associated with Ki-67 expression. miR-125b couldinhibit cell proliferation, cell cycle progression and metastasis of HCC cells.Moreover, the onco-gene LIN28B was identified as a direct and functional targetfor miR-125b in hepatic carcinogenesis. miR-26a directly represses expression of cyclinD2 and cyclin E2miR-26a expression induces a G1arrest in human liver cancer cells After binding to target mRNAs,miRNAs form a complex with them and reduce their protein levels, eitherby degrading the mRNA or bysuppressing the translation of the target genexxxiv.It has been reported that miRNAs can post transcriptionally regulate ?30% ofhuman genes, suggesting that miRNAs may have pivotal roles in physiological andpathological processes, including human carcinogenesisxxxv.Over the past 5 years, emerging evidence has demonstrated that miRNAs arecrucial for the initiation, promotion, and progression of human cancers.
miR-125bmiR-125b is under expressed inmost cases of HCC and is inversely related to cell proliferation index in HCC.miR-125b can suppress cell growth, induce cell cycle arrest at G1 phase, andinhibit migration and invasion of HCC cells. These tumor-suppressive functionsof miR-125b are mediated by the target gene LIN28B, a potential oncogene inHCC. These findings facilitate a better understanding of the molecularpathogenesis of HCC and suggest that miR-125b might be a candidate for thetreatment of HCC.
xxxviIt has been reported thatAAV-mediated miR-26a had therapeutic effects in vivo in a murine liver cancermodelxxxvii.expression of miR-125b was suppressedin about 70% of primary HCCsFurthermore, enforced expressionof LIN28B significantly counteracted the G1 arrest induced by miR-125our results showed that miR-125bcould significantly suppress HCC cell pro-liferation in vitro and in vivo. Inaddition, our results demonstrated that miR-125b is a potential metastasissuppressor for HCC, because overexpression of miR-125b can significantlyinhibit HCC cell migration and invasion. Altogether, the suppressive effects ofmiR-125b on HCC cell growth and metastasis might con-tribute to the poorprognosis of HCC patients with low expression of miR-125b.
xxxviiiThe mechanistic insight into theinhibitory effects of miR-125b on cell proliferation indicated that miR- 125bcan induce cell cycle arrest at the G1/S transition of HCC cells, suggestingthat down-regulation of miR-125b in HCC may facilitate the cancer cells todivide and grow quickly.Other miRNAsmiR-127It was proved that DNAdemethylation and histone deacetylase inhibition can activate expression ofmiR-127, which may act as a tumor suppressor by targeting the B-cellleukemia/lymphoma 6 proto-oncogene.xxxixIt is used as a biomarker for the detection of liver cancer in the serum, it’sunder- expression confirms the presence of the liver cancermiR-1Analogously, promoter methylationwas shown to be responsible for the down regulation of miR-1 in HCCxl,that is used as a biomarker for the detection of liver cancer in the serum,it’s under- expression confirms the presence of the liver cancer miR-34aoverexpression of miR-34a in HCCmight be due to a general status of hypomethylationxlithat is used as a biomarker for the detection of liver cancer in the serum,it’s over- expression confirms the presence of the liver cancerMiR-1MiR-1 is the other microRNA thatis used as a biomarker for the detection of liver cancer in the serum, it’sunder- expression confirms the presence of the liver cancer. xliimiR-10bMiR-10b is the other microRNAthat is used as a biomarker for the detection of liver cancer in the serum,it’s over- expression confirms the presence of the liver cancer. xliiimiR-17MiR-17 is the other microRNA thatis used as a biomarker for the detection of liver cancer in the serum, it’sunder- expression confirms the earlyDiagnosis of the liver cancer. xlivmiR-20bMiR-20b is the other microRNAthat is used as a biomarker for the detection of liver cancer in the Plasma, it’s under- expression confirmsthe presence of the liver cancerxlv.
miR-21MiR-21 is the other microRNA thatis used as a biomarker for the detection of liver cancer in the Sputum or BAL, it’s under- expressionconfirms the presence of the liver cancerxlvi.While if it is detected in serum inover-expressive form then it confirms the prognosis of liver cancerxlvii miR-22MiR-22 is the other microRNA thatis used as a biomarker for the detection of liver cancer in the serum, it’s under- expression confirmsthe early diagnosis of the livercancerxlviii.While if it is reported in over-expressive form, then it will confirm theprognosis of cancer tooxlix.If it shown as underexpressed in Pleural effusion then it confirms thediagnosis of liver cancer. l MiR-28-5pMiR-28-5p is another miRNA thatif shows underexpression in serum, then early diagnosis of liver cancer isconfirmed.
li miR29aMiR-28-5p is another miRNA thatif shows over-expression in serum, than earlydiagnosis of liver cancer is confirmed. liiConclusion:Although deregulation of miRNAshas been frequently observed in tumor tissues (3, 4), little is known about themolecular mechanisms by which miRNAs modulate the process of tumorigenesis andthe behavior of cancer cells.liiiThe causes of the widespread miRNA mis-expression in cancers are not clearlyunderstood; (in this conclusion write what u entered inur abstract) i