Site Loader

Role of miRNA in liver cancer
(HCC)

MicroRNAs (miRNAs), discovered by
Ambros and colleagues in 1993,i
are small noncoding RNAs, 18–24 nucleotides in length, that regulate gene
expression by binding to mRNAs to interfere with the process of translation.ii
Genes that encode miRNAs are transcribed from DNA to a primary transcript
(pri-miRNAs), which is processed into a short precursor (pre-miRNA) and then
exported into the cytoplasm where it is further processed into a mature, single
stranded miRNAiii.
Most miRNAs are transcribed from intergenic regions by RNA
polymerase II. The primary transcripts are precursor molecules (pri-miRNA) that
are processed by two ribonucleases—Drosha in the nucleus and Dicer in the
cytoplasm—into mature miRNAs.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

MiRNAs are endogenous and potentially can regulate every aspect of
cellular activity, including development and proliferation, differentiation,
metabolism, viral infection, epigenetic modulation, apoptotic cell death, and
tumor genesis. Recent studies provide evidence that miRNAs are abundant in the
liver and affect a diverse spectrum of liver functions.iv

Different
classes of miRNAs can play oncogenic as well as tumor-suppressing roles; the
same group of miRNAs can exhibit oncogenic activity in one tissue type but act
as a tumor suppressor in anotherv

miRNAs potently influence
cellular behavior through the regulation of extensive gene expression networksvi
vii.

It has been demonstrated that
most tumors are characterized by globally diminished miRNA expressionviii.

MicroRNAs, small noncoding RNAs
that regulate the translation of many genes, are excellent biomarkers for
cancer diagnosis and prognosisix

Chronic infections with either
HBV or HCV increase the relative risk of liver cancer greatly. These chronic
viral infections are present in more than 70% of HCC cases, and iatrogenic
interventions against these viruses significantly reduce the risk of HCC
development.x

Methods of Cancer diagnosis:

Biological samples such as blood,
serum, stool, pancreatic juice or urine, as well as both DNA and RNA, have been
analyzed 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 or
circulating cancer cells in blood samples have been evaluated to allow the
early diagnosis of cancer patients. Recently, epigenetic changes such as gene
methylation in biological samples from cancer patients have also been analysed.
In addition, serum levels of certain proteins involved in tumour biology such
as cathepsin B, E-cadherin, hepatocyte growth factor, interleukins, and other
cytokines and hormones have been measured in the serum of cancer patients. However, none of these analysis methods has
yet shown adequate sensitivities and specificities to facilitate the detection
of cancer in its early stagesxi

miRNA in Cancer Diagnosis:

MicroRNAs (miRNAs), discovered by
Ambros and colleagues in 1993,xii1
are small noncoding RNAs, 18–24 nucleotides in length, that regulate gene
expression by binding to mRNAs to interfere with the process of translation.xiii2
Genes that encode miRNAs are transcribed from DNA to a primary transcript
(pri-miRNAs), which is processed into a short precursor (pre-miRNA) and then
exported into the cytoplasm where it is further processed into a mature, single
stranded miRNAxiv.
Most miRNAs are transcribed from intergenic regions by RNA
polymerase II. The primary transcripts are precursor molecules (pri-miRNA), are
capped, polyadenylated and are usually several thousand bases in lengthxv, that are processed by two ribonucleases—Drosha in the nucleus
and Dicer in the cytoplasm—into mature miRNAsxvi. Dicer is involved in formation of a transient 22 nt
mature double stranded (ds) miRNA (miRNA duplex). Dicer initiates the formation
of the RNA-induced silencing complex (RISC), which is responsible for gene
silencing.xvii

miRNAs potently influence
cellular behavior through the regulation of extensive gene expression networksxviii
xixhence
they potentially regulate every aspect of cellular activity, including
development and proliferation, differentiation, metabolism, viral infection,
epigenetic modulation, apoptotic cell death, and tumor genesis.xx

It has been demonstrated that
most tumors are characterized by globally diminished miRNA expressionxxi.Different classes of miRNAs can play oncogenic as well as
tumor-suppressing roles; the same group of miRNAs can exhibit oncogenic
activity in one tissue type but act as a tumor suppressor in anotherxxii

MicroRNAs, small noncoding RNAs that regulate the
translation of many genes, are excellent biomarkers for cancer diagnosis and
prognosisxxiii.
Due to advances in oncology, most cancers are diagnosed in advanced stages,
leading to poor outcomes.

Several aspects of miRNAs
including their intricate nature of interaction with multiple targets and
multiple pathways make them extremely useful potential agents for clinical
diagnostics.

The study of miRNA SNPs and
miRNA-binding site SNPs as biomarkers of cancer risk is another way in which
miRNAs may open up new avenues, allowing early cancer detection.

 

MicroRNA can be used in five
different ways for the diagnosis of cancer:

1.       One
can use the micro-RNA for the detection of cancer at very earlier stages; this
is done by using blood out of the patient’s body. Profiling this blood or using
tumor derived exosomal miRNAs this gives you the benefit of avoiding the other
invasive methods.

2.       They
can also be used in the prediction of cancer predisposition, this is done by
two different ways which includes; studying the phenomenon of SNPs (abbreviated
as Single Nucleotide Polymorphism) in the gene of miRNA, study the binding site
of miRNA in mRNA.

3.       MiRNA
can also be used in determination of subtypes of one cancer hence it is used to
distinguish between various subtypes of cancer. In this method we use such
miRNA that gives differential expression in different types of cancer.

4.       miRNA
can 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 is
correlated with intrahepatic metastasis of HCC and increases HCC cell migration
and invasion by directly targeting RhoGDIAxxiv

 

 

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 featuresxxv

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.xxvi

 

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.xxvii

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 hepatocytesxxviii

 

 

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.xxix

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 miRNAxxx.

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 survivalxxxi

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

coding genes are predicted miRNA
targets7,8xxxii

 

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 inflammationxxxiii

 

 

 

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

was suppressed in about 70% of
primary HCCs and was highly associated with Ki-67 expression. miR-125b could
inhibit cell proliferation, cell cycle progression and metastasis of HCC cells.
Moreover, the onco-gene LIN28B was identified as a direct and functional target
for miR-125b in hepatic carcinogenesis.

 

miR-26a directly represses expression of cyclin
D2 and cyclin E2

miR-26a expression induces a G1
arrest in human liver cancer cells

 

 

 

After binding to target mRNAs,
miRNAs form a complex with them and reduce their protein levels, either

by degrading the mRNA or by
suppressing the translation of the target genexxxiv.
It has been reported that miRNAs can post transcriptionally regulate ?30% of
human genes, suggesting that miRNAs may have pivotal roles in physiological and
pathological processes, including human carcinogenesisxxxv.
Over the past 5 years, emerging evidence has demonstrated that miRNAs are
crucial for the initiation, promotion, and progression of human cancers.

 

 

miR-125b

miR-125b is under expressed in
most 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, and
inhibit migration and invasion of HCC cells. These tumor-suppressive functions
of miR-125b are mediated by the target gene LIN28B, a potential oncogene in
HCC. These findings facilitate a better understanding of the molecular
pathogenesis of HCC and suggest that miR-125b might be a candidate for the
treatment of HCC.xxxvi

It has been reported that
AAV-mediated miR-26a had therapeutic effects in vivo in a murine liver cancer
modelxxxvii.

expression of miR-125b was suppressed
in about 70% of primary HCCs

Furthermore, enforced expression
of LIN28B significantly counteracted the G1 arrest induced by miR-125

our results showed that miR-125b
could significantly suppress HCC cell pro-liferation in vitro and in vivo. In
addition, our results demonstrated that miR-125b is a potential metastasis
suppressor for HCC, because overexpression of miR-125b can significantly
inhibit HCC cell migration and invasion. Altogether, the suppressive effects of
miR-125b on HCC cell growth and metastasis might con-tribute to the poor
prognosis of HCC patients with low expression of miR-125b.xxxviii

The mechanistic insight into the
inhibitory effects of miR-125b on cell proliferation indicated that miR- 125b
can induce cell cycle arrest at the G1/S transition of HCC cells, suggesting
that down-regulation of miR-125b in HCC may facilitate the cancer cells to
divide and grow quickly.

Other miRNAs

miR-127

It was proved that DNA
demethylation and histone deacetylase inhibition can activate expression of
miR-127, which may act as a tumor suppressor by targeting the B-cell
leukemia/lymphoma 6 proto-oncogene.xxxix
It 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-1

Analogously, promoter methylation
was 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-34a

overexpression of miR-34a in HCC
might be due to a general status of hypomethylationxli
that 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

MiR-1

MiR-1 is the other microRNA 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. xlii

miR-10b

MiR-10b is the other microRNA
that 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. xliii

miR-17

MiR-17 is the other microRNA that
is used as a biomarker for the detection of liver cancer in the serum, it’s
under- expression confirms the early
Diagnosis of the liver cancer. xliv

miR-20b

MiR-20b is the other microRNA
that is used as a biomarker for the detection of liver cancer in the Plasma, it’s under- expression confirms
the presence of the liver cancerxlv.

miR-21

MiR-21 is the other microRNA that
is used as a biomarker for the detection of liver cancer in the Sputum or BAL, it’s under- expression
confirms the presence of the liver cancerxlvi.
While if it is detected in serum in
over-expressive form then it confirms the prognosis of liver cancerxlvii

 

miR-22

MiR-22 is the other microRNA that
is used as a biomarker for the detection of liver cancer in the serum, it’s under- expression confirms
the early diagnosis of the liver
cancerxlviii.
While if it is reported in over-expressive form, then it will confirm the
prognosis of cancer tooxlix.
If it shown as underexpressed in Pleural effusion then it confirms the
diagnosis of liver cancer. l

 

MiR-28-5p

MiR-28-5p is another miRNA that
if shows underexpression in serum, then early diagnosis of liver cancer is
confirmed. li

 

miR29a

MiR-28-5p is another miRNA that
if shows over-expression in serum, than early
diagnosis of liver cancer is confirmed. lii

Conclusion:

Although deregulation of miRNAs
has been frequently observed in tumor tissues (3, 4), little is known about the
molecular mechanisms by which miRNAs modulate the process of tumorigenesis and
the behavior of cancer cells.liii
The causes of the widespread miRNA mis-expression in cancers are not clearly
understood; (in this conclusion write what u entered in
ur abstract)

 

 

 

i

Post Author: admin

x

Hi!
I'm Lewis!

Would you like to get a custom essay? How about receiving a customized one?

Check it out