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 featuresiMiR-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.
ii 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.
iiiCAT-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 hepatocytesiv 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.
vKota 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 miRNAvi.
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 survivalviiis postulated that about 1%-5% ofgenes in ani-mals encode miRNAs, while 10%-30% of protein-coding genes are predicted miRNAtargets7,8viii 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 inflammationix 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-125biLoss of miR-122 expression in liver cancer correlates with suppression of thehepatic phenotype and gain of metastatic properties. ii Downregulation of miR-122 in therodent and human hepatocellular carcinomas.Kutay H, Bai S, Datta J, Motiwala T,Pogribny I, Frankel W, Jacob ST, Ghoshal K iii Cyclin G1 is a target of miR-122a, amicroRNA frequently down-regulated in human hepatocellular carcinoma.
Gramantieri L, Ferracin M, FornariF, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, GraziGL, Croce CM, Bolondi L, Negrini M iv miR-122, a mammalian liver-specificmicroRNA, is processed from hcr mRNA and may downregulate the high affinitycationic amino acid transporter CAT-1.Chang J, Nicolas E, Marks D, SanderC, Lerro A, Buendia MA, Xu C, Mason WS, Moloshok T, Bort R, Zaret KS, Taylor JM v https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3406571/vi Therapeutic microRNA deliverysuppresses tumorigenesis in a murine liver cancer model.Kota J, Chivukula RR, O’Donnell KA,Wentzel EA, Montgomery CL, Hwang HW, Chang TC, Vivekanandan P, Torbenson M, ClarkKR, Mendell JR, Mendell JT vii MicroRNA expression, survival, andresponse to interferon in liver cancer.Ji J, Shi J, Budhu A, Yu Z, ForguesM, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, LeeJ, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW viiiKrek A, Grun D, Poy MN, Wolf R, Rosenberg L, EpsteinEJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M,Rajewsky N. Combinatorial microRNA target predictions.
Nat Genet 2005; 37: 495-5008 Lewis BP, Burge CB, Bartel DP. Conserved seed pairing,often flanked by adenosines, indicates that thousandsofhuman genes are microRNA targets. Cell 2005; 120: 15-20ixHand NJ, Master ZR, Le Lay J, Friedman JR. Hepaticfunction is preserved in the absence of maturemicroRNAs.Hepatology 2009; 49: 618-626