الفهرس 
Epidemiology of Hepatocellular CarcinomaOnly 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma (HCC) is a global health
problem, with over 700,000 new cases worldwide each year. The
prognosis of HCC patients remains poor. In Egypt, HCC accounts
for about 4.7 of chronic liver disease patients. Thus, it is necessary
to search for markers that can be used in early screening or
prognosis in an attempt to improve the clinical management of
HCC patients.
The mitogen-activated protein kinase (MAPK) pathway is
one of the pathways that are commonly activated in cancer. Dualspecificity protein kinase (DUSP) phosphorylates tyrosine and
threonine residues in a TXY motif of MAPK, leading to full MAPK
activation. MAPK phosphatase-7 (MKP7) or (DUSP16) was
identified as a JNK-specific phosphatase. However, despite its high
specificity for JNK, MKP7 interacts also with ERK. There are three
JNK-coding genes have been identified in mammals: JNK1, JNK2,
and JNK3. JNK3 is selectively expressed in neuronal tissues while
JNK1 and JNK2 are ubiquitously expressed. JNK has been widely
implicated in some physiological processes, including embryonic
development, cell survival/apoptosis, and proliferation and
production of inflammatory cytokines.
Recently some studies found a relation between the miRNA
regulation and some MAPK activity. For example, the upregulations of mir-24 inhibit DUSP16 (MKP7), which activates
downstream signaling of JNK and alters myeloid cells and
differentiation. Abnormal MAPK signaling has important
consequences on the development and progression of human
cancer.
The objective of the present study was to understand the
role of some miRNAs in the regulation of MAPK pathway in HCC
of Egyptian patients; this achieved through: 1) Detection of the
expression level of miRNAs targeting DUSP16 (MKP7) and JNK
family (JNK1, JNK2, and JNK3) using quantitative Real-Time PCR
(qRT-PCR) technique. 2) Detection of the protein levels of
DUSP16, JNK1 and JNK2 using immunohistochemistry (IHC)
assay. 3) To find a correlation between specific miRNAs and HCC
cases. 4) Determination of specific miRNA that could be used as
diagnostic markers for HCC patients.
A highly significant downregulation was identified in JNK2
and JNK3 gene expression in HCC patients as compared to controls
with (P value = 0.016, 0.000) respectively, on the other hand, there
is no significant change was detected in DUSP16 and JNK1 gene
expression. A strong positive correlation was recorded between the
mRNA expression of DUSP16 and each of JNK1, JNK2, and JNK3
genes (P value less than 0.001) for each. In addition, we found 10
miRNAs, miR-18b; miR-30c; miR-30e; miR-99a; miR-126; miR-
194; miR-198; miR-215; miR-455 and miR-455-3p showed significant correlation with mRNA genes of DUSP16, JNK1, JNK2
and JNK3 (P value less than 0.05). Absence of protein expression
was detected for DUSP16, JNK1, and JNK2 in all normal tissue
samples. Whereas in HCC cases, 34% (13 out 38) showed DUSP16
protein expression (P ≤ 0.0001). 82% (31 out 38) for JNK1 (P
≤0.0001) and 71% (27 out 38) showed JNK2 protein expression (P
≤ 0.0001) which are statistically strong significant between cases
and controls.
These results provide a resource for studying the role of
miRNAs in HCC patients and contribute to a better understanding
of the physiological significance of miRNAs in the regulation of
MAPK pathway. The miRNAs considered as a novel class of
biomarkers because they have a specific signature with the disease.
The high mortality rate of HCC is because the detection at
late stage and limited therapeutic options. The clinical
heterogeneity of HCC and the deficiency of good diagnostic
markers and treatment strategies have condensed the disease a
major challenge. And the MAPK gene and protein expression also
play an important role in HCC as a therapeutic agent regulated by
miRNAs.