miR-122 up to 70% of human HCCs. miR-122

miR-122

One of the most abundant miRNAs
in the liver is miR-122a. It is expressed in normal hepatocytes but is
downregulated in up to 70% of human HCCs. miR-122 loss was also associated with
high proliferation and low apoptotic featuresi

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MiR-122 is described as a
liver-specific miRNA. The expression of miR-122 can be used as a marker of
liver development and it undergoes liver-specific expression during embryonic
development. A role for miR-122 in hepatocarcinogenesis is suggested by the
differential expression of miR-122a in HCC versus non-tumor cirrhotic hepatic
tissue, and by the studies by Kutay et al of miRNA expression in murine HCC. In
these studies, miR-122a was decreased by 50% in patients of HHC.ii

 

Cyclin G1 promotes cell cycle
progression and it may be associated with genomic instability. In HCC cells, an
inverse correlation has been observed between miR122a and cyclin G1, which is a
validated target of this miRNA. In experimental hepatocarcinogenesis, loss of
cyclin G1 is associated with a significantly lower tumor incidence after
carcinogenic challenges. Thus, deregulated expression of cyclin G1, in response
to altered miR122a expression, could contribute to the pathogenesis of liver
cancer.iii

CAT-1 is a carrier protein
required in the regenerating liver for the transport of cationic amino acids
and polyamines in the late G1 phase, a process that is essential for liver
cells to enter mitosis.Given these data, modulation of expression of CAT-1 may
be another mechanism through which this miRNA regulates cell cycle in normal
and transformed hepatocytesiv

 

 

studies have shown the
involvement of miRNAs in the regulation of HCV infection. MiR-122 is first
identified liver-specific cellular miRNA, which has been shown to enhance the
replication of HCV by targeting the viral 5′ non-coding region48 . It appears
that HCV replication is associated with an increase in expression of
cholesterol biosynthesis genes that are regulated by miR-122 and hence is
considered as a potential target for antiviral intervention49

 

 

miR26, and miR-223

 

miR26:

Numerous tumors and normal
tissues exhibit different expression of miR-26 during growth, development and
tumorigenesis and miR-26 may participate in various biological processes
through imperfect sequence complementarity binding between seed region and 3?UTR
of target mRNA. miR-26 may repress the target gene translation and decrease
expression levels of target gene-coding protein.

t has been observed that
expression of miR-26 is disordered in many tumors and that it has specific
functions in different tumors.v

Kota et
al reported that the expression of miR-26 was down-regulated in
hepatocellular carcinoma (HCC) cells and that overexpression of miR-26a in
liver cancer cells in vitro induced
an 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 this
miRNA to a mouse model of HCC using adeno-associated virus resulted in the
inhibition of cancer cell growth and proliferation, and increased
tumor-specific apoptosis. This process indicated that miR-26a was a
tumor-suppressor miRNAvi.

Expression of miR-26 was
down-regulated in tumors compared with paired non-cancerous tissues, indicating
that the sexpression of miR-26 was associated with HCC.. Moreover, tumors with
a reduced miR-26 expression exhibited a distinct transcriptomic pattern and
activated the signaling pathways between nuclear factor ?B and interleukin-6,
which may play a role in tumor development according to gene networks
information. Patients with a lower miR-26 expression in HCC had a shorter
survival but a more favorable response to interferon therapy than those with a
higher miR-26 expression in HCC, indicating that miR-26 was associated with
post-operative survivalvii

is postulated that about 1%-5% of
genes in ani-mals encode miRNAs, while 10%-30% of protein-

coding genes are predicted miRNA
targets7,8viii

 

The importance of miRNAs in the
liver immune system is highlighted by the fact that mice lacking Dicer 1
function in the liver were unable to produce mature miRNA and showed
progressive hepatocyte damage, apoptosis, and portal inflammationix

 

 

 

China alone accounts for more
than 50% of HCC incidence in the world.8

84 miRNAs were differentially
expressed in HCC versus nontumorous liver tissues, and only miR-125b expression
was associated with patients’ survival.10

expression of miR-125b

i
Loss of miR-122 expression in liver cancer correlates with suppression of the
hepatic phenotype and gain of metastatic properties.

 

ii Downregulation of miR-122 in the
rodent 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, a
microRNA frequently down-regulated in human hepatocellular carcinoma.

Gramantieri L, Ferracin M, Fornari
F, Veronese A, Sabbioni S, Liu CG, Calin GA, Giovannini C, Ferrazzi E, Grazi
GL, Croce CM, Bolondi L, Negrini M

 

iv miR-122, a mammalian liver-specific
microRNA, is processed from hcr mRNA and may downregulate the high affinity
cationic amino acid transporter CAT-1.

Chang J, Nicolas E, Marks D, Sander
C, 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 delivery
suppresses 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, Clark
KR, Mendell JR, Mendell JT

 

vii MicroRNA expression, survival, and
response to interferon in liver cancer.

Ji J, Shi J, Budhu A, Yu Z, Forgues
M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, Qin LX, Man K, Lo CM, Lee
J, Ng IO, Fan J, Tang ZY, Sun HC, Wang XW

 

viii
Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein

EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M,

Rajewsky N. Combinatorial microRNA target predictions.

Nat Genet 2005; 37: 495-500

8 Lewis BP, Burge CB, Bartel DP. Conserved seed pairing,

often flanked by adenosines, indicates that thousands
of

human genes are microRNA targets. Cell 2005; 120: 15-20

ix
Hand NJ, Master ZR, Le Lay J, Friedman JR. Hepatic

function is preserved in the absence of mature
microRNAs.

Hepatology 2009; 49: 618-626

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