الفهرس 
I-IntroductionOnly 14 pages are availabe for public view
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Abstract
Hepatocellular carcinoma (HCC) is the fifth cause of cancer death in the world. Most HCC cases are diagnosed at advanced stages when curative therapies are of limited efficacy. De novo lipogenesis (DNL) has been reported to play a central role in progression of various human cancers and HCC. Therefore, targeting DNL pathway using statins could improve response to antiviral treatments, decrease progression of liver fibrosis and improve treatment of HCC.
Sterol regulatory element binding proteins (SREBPs) family includes SREBP1a, c and SREBP2 are the key regulators of DNL pathway. Their activation increases the expression of fatty acid synthase (FASN) and myelocytomatosis virus cellular homolog (c-MYC). SREBP2 activates 3-hydroxy-3-methyl-glutaryl coenzyme-COA (HMG-CoA) reductase, the rate limiting enzyme for cholesterol synthesis which activates c-MYC, while SREBP1a activates mainly FASN. However, overlapping between specificities could occur.
Therefore, the aim of this study was to characterize the immunohistochemical (IHC) expression of SREBP1a, SREBP2, FASN and c-MYC in non-alcoholic fatty liver disease (NAFLD), chronic viral hepatitis, cirrhosis and HCC and to delineate the correlation between these markers in the studied groups. In addition, the current study was aimed to correlate markers expression with the clinico-pathological data to identify their clinical significance.
This was a retrospective and prospective, cases control study. The study included 100 HCC cases with 95 corresponding adjacent non-tumor liver tissues, 50 liver cirrhosis cases, 50 chronic viral hepatitis cases, 20 NAFLD cases and 20 normal liver tissues. All specimens were obtained from Egyptian patients
The current study showed low expression of SREBP1a, SREBP2, FASN and c-MYC in normal control group. Additionally, SREBP1a nuclear (mature) expression was negatively regulated by the effect of increased FASN expression. Also, SREBP2 cytoplasmic expression compensated for low SREBP1a expression.
In the present study, SREBP1a cytoplasmic (precursor) and mature, SREBP2 cytoplasmic and FASN were overexpressed in NAFLD group. However, c-MYC expression was not significantly related to NAFLD. Additionally, SREBP1a mature and SREBP2 cytoplasmic overexpression was associated with the presence of lobular inflammation. However, there was no significant association between both FASN and c-MYC and the clinico-pathological data of NAFLD group. Also, there was no significant correlation between the studied markers within the NAFLD group.
The current study showed significant overexpression of the four studied markers in chronic hepatitis group. The expression of SREBP2, FASN and c-MYC was significantly associated with hepatitis C virus (HCV) rather than hepatitis B virus (HBV). Additionally, the expression of SREBP1a and c-MYC was significantly low in chronic hepatitis patients with concomitant metabolic syndromes. Furthermore, there was a complementary/ alternative role of SREBP1a and SREBP2 to maintain high FASN expression and hepatocytes steatosis in chronic hepatitis and cirrhosis group. Similarly, SREBP2 regulated the expression of cholesterogenic (c-MYC) and lipogenic (FASN) proteins in chronic hepatitis group.
Additionally, the present study showed significant associations between SREBP1a mature, SREBP2 and c-MYC (cytoplasmic and nuclear) and the high histopathological activity of chronic liver disease. However, SREBP1a mature expression was associated with mild HAI in cirrhosis group. Furthermore, SREBP1a, FASN and c-MYC were associated with development of liver fibrosis.
The current study found no significant association between SREBP1a, FASN and c-MYC and the etiology of HCC. However, SREBP2 expression was significantly related to HCV throughout the process of hepatocarcinogenesis.
The present study found significant overexpression of SREBP1a precursor, SREBP2, FASN and c-MYC cytoplasmic and nuclear in HCC cases in comparison with normal control group. Furthermore, the expression of SREBP1a (precursor and mature) and FASN expression was upregulated in HCC in comparison with the adjacent non-tumor liver, while SREBP2 cytoplasmic expression was significantly higher in the adjacent non-tumor liver in comparison with HCC.