الفهرس 
ACKNOWLEDGEMENT
NORMAL LIVEROnly 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma (HCC) is the third most common neoplasm worldwide and represents the second leading cause of cancer-related mortality. In Egypt, HCC is a common malignancy rankingthe second most common cancer in men and the sixth most common cancers in women.Up to 90% of HCC in Egypt wasattributed to HCV infection.Ezrin and ICAM-1 are essential cellular signaling molecules that involved in the process of tumorigenesis of many cancers. The aim of the present work was to investigate the up-regulation of ezrin and ICAM-1 through transition from CHC, cirrhosis to HCC and the correlation between them in the study groups.
This study was carried out on a total number of 95 specimens;they were obtained retrospectively from December 2007 till January 2011 and prospectively from February 2011 till December 2013from Surgical Pathological Laboratory, Assiut University Hospitals, Faculty of Medicine, Assiut University and Surgical Pathological Laboratory, South Egypt National Cancer Institute, Assiut University. All of these specimens were obtained from HCV positive and HBV negative patients and grouped as: Group I: 47HCC specimens, Group II: 19 HCV related liver cirrhosis specimens. Group III: 18 chronic hepatitis C (CHC) specimens. Group IV: 11normal liver specimens(as controls).The expression of ezrin and ICAM-1 in all groups was examined by immunohistochemical method and scored by Immunoreactivity score (IRS).Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS version 16.0).
In the present study, there was significant increase in the mean age of patients in transition from CHC to cirrhosis to HCC groups (P<0.01).The frequency of CHC, cirrhosis, and HCC was significantly higher in males than in females(P< 0.01).
There was significant increase in ezrin IRS in CHC and HCC groups as compared to control group (P<0.01). However, insignificant increase was present in cirrhosis group(P=0.687).Among HCC specimensshowed cirrhosis adjacent to HCC tissues, there was highly significant increase in ezrin IRS in HCC tissues than adjacent cirrhosis (P< 0.001). Correlations betweenezrin expression and clinicopathological characters of HCC group showed significant positive correlation between ezrin expression and high serum AFP, large tumor size, high tumor grade, and vascular invasion and insignificant positive correlation with tumor site, number of tumor masses, histological pattern, growth pattern, and capsular invasion.
As regardsICAM-1 expression, There was significant increase in ICAM-1 IRS in the study groups as compared to control group (P<0.001).Among HCC specimensshowed cirrhosis adjacent to HCC tissues, there was highly significant increase in ICAM-1 IRS in HCC tissues than adjacent cirrhosis (P<.001). Correlations betweenICAM-1 expression and clinicopathological characters of HCC group showed significant positive correlation between ICAM-1 expression and both high serum AFP and vascular invasion and insignificant positive correlation with tumor size, tumor site, number of tumor masses, histological grade, histological pattern, growth pattern, and capsular invasion.
Correlation between Ezrin and ICAM-1 immunoreactivity in the study groups showed thatboth ezrin and ICAM-1 IRS were low in normal liver with considerable increase in the mean of ezrin IRS in CHC group, while mean of ICAM-1 IRS was minimally increased. Both ezrin and ICAM-1 IRS showed considerable increase in transition from cirrhosis to HCC. In cirrhosis and HCC groups, there was considerable correlation between ezrin and ICAM-1 staining but no correlation between ezrin and ICAM-1 staining in CHC group.This positive correlation between ezrin and ICAM-1 expression in HCC can be interpreted in the view of ability of activated ezrin molecule to increase expression of ICAM-1 protein which promotes HCC pathogenesis. Ezrin is a highly regulated protein which exists in the cytoplasm as one of two forms either dormant (inactive) or active. Ezrin is normally present in dormant form.Sustained and prolonged degeneration and regeneration of hepatocytes leads to activation of ezrin.This activationunmasks the F-actin binding sites which have the ability to bind with cytoplasmic tails of ICAM-1 protein.An interaction between ezrin and ICAM-1 facilitates post-binding events; ICAM-1 enhances binding of HGF to c-Met receptor that leads to activation of c-Met pathway in progenitor/stem cells. Activation of c-Met pathway stimulates multiple oncogenic pathwayswhich have a major role in HCC pathogenesis and angiogenesis,so ICAM-1 is a novel co-receptor for c-Met transduction signalling pathway. Moreover, both ezrin and ICAM-1 have a pivotal role in pathogenesis and angiogenesis of HCC through regulation of many other transduction signalling pathwaysincluding Hedgehog, Erk (RhoA), PI3K/Akt/ mTOR, NF-κB pathway, TGF-β, IL-6/STAT3, and anti-apoptotic pathways.