Original Article
Copyright ©2010 Baishideng. All rights reserved.
World J Hepatol. Jan 27, 2010; 2(1): 32-41
Published online Jan 27, 2010. doi: 10.4254/wjh.v2.i1.32
Differential expression of cell cycle regulators in HCV-infection and related hepatocellular carcinoma
Azza E El Bassiouny, Mona M Nosseir, Mona K Zoheiry, Noha A Ameen, Ahmed M Abdel-Hadi, Ibrahim M Ibrahim, Suher Zada, Abdel-Hakeem Saad El-Deen, Nora E El-Bassiouni
Azza E El Bassiouny, Mona K Zoheiry, Department of Immunology, Theodor Bilharz Research Institute, PO Box 30 Imbaba, Giza 12411, Egypt
Mona M Nosseir, Ahmed M Abdel-Hadi, Department of Pathology, TBRI, PO Box 30 Imbaba, Giza12411, Egypt
Noha A Ameen, Central Laboratory, Theodor Bilharz Research Institute, PO Box 30 Imbaba, Giza 12411, Egypt
Ibraheim M Ibrahim, Department of Hepato-Gastroenterology, Theodor Bilharz Research Institute, PO Box 30 Imbaba, Giza 12411, Egypt
Suher Zada, Biology Department, American University, PO Box 74, New Cairo 11835, Egypt
Abdel-Hakeem Saad El-Deen, Zoology Department, Faculty of Science, Cairo University, Giza 12411, Egypt
Nora E El-Bassiouni, Zoology Department, Faculty of Science, Cairo University, Giza 12613, Egypt
Author contributions: El Bassiouny AE and El-Bassiouni NE: construction of the plan and design of work, interpretation and discussion of results, writing and revising the manuscript and financial support; Nosseir MM: interpretation and discussion of the results of histopathological and Immunohistochemical studies, close supervision of the different sets of immunohistochemistry, writing and revising the text; Zoheiry MK: help in performance of laboratory investigations, collection of data, writing and revising the manuscript; Ameen NA: collection of data, help in interpretation and discussion of the results. Performance of laboratory investigations and immunohistochemical staining; Abdel-Hadi AM: scientific interpretation of results of liver biopsies; Ibraheim IM: Providing clinical data and liver biopsy specimens; Zada S: scientific and financial support; Saad El-Deen AH: scientific supervision of the work.
Supported by Theodor Bilharz Research Institute (Grant # 74D) in collaboration with the American University of Cairo
Correspondence to: Dr. Mona M Nosseir, Professor of Pathology, Pathology Department, Theodor Bilharz Research Institute 12411, PO Box 30 Imbaba, Giza 12411, Egypt. drmonanosseir@yahoo.com
Telephone: +20-2-35401019 Fax: +20-2-35408125
Received: March 9, 2009
Revised: October 10, 2009
Accepted: October 17, 2009
Published online: January 27, 2010

AIM: To investigate cell cycle proteins in chronic hepatitis C virus infection in order to analyze their role in the process of hepatocyte transformation and to characterize their prognostic properties.

METHODS: Subjects of the current study included 50 cases of chronic hepatitis C (CHC) without cirrhosis, 30 cases of CHC with liver cirrhosis (LC), and 30 cases of hepatitis C-related hepatocellular carcinoma (HCC) admitted to the Department of Hepato-Gastroenterology, Theodor Bilharz Research Institute (TBRI), Giza, Egypt. Fifteen wedge liver biopsies, taken during laparoscopic cholecystectomy, were also included as normal controls. Laboratory investigations including urine and stool analysis, liver function tests and prothrombin concentration; serologic markers for viral hepatitis and ultrasonography were done for all cases of the study together with immunohistochemical analysis using primary antibodies against Cyclin D1, Cyclin E, p21, p27 and Rb/p105 proteins.

RESULTS: Normal wedge liver biopsies didn’t express Cyclin E or Rb/p105 immunostaining but show positive staining for Cyclin D1, p21 and p27. Cyclin D1 expressed nuclear staining that was sequentially increased from CHC to LC (P < 0.01) to HCC (P < 0.001) cases; meanwhile, Cyclin E revealed nuclear positivity only in the case of HCCs patients that was directly correlated to Rb/p105 immuno-reactivity. The expression of p21 and p27 was significantly increased in CHC and LC cases compared to normal controls and HCCs with no significant difference between well- and poorly-differentiated tumors. p21 showed only a nuclear pattern of staining, while, p27 presented with either cytoplasmic and/or nuclear reactivity in all studied cases. Correlation analysis revealed a direct relation between Cyclin D1 and p21 in CHC cases (P < 0.001), between Cyclin D1 and Cyclin E in HCCs (P < 0.01); however, an inverse relationship was detected between Cyclin D1 and p21 or p27 (P < 0.001) and between p21 and Rb/p105 (P < 0.05) in HCCs.

CONCLUSION: Upregulation of Cyclin D1 in CHC plays a vital role in the development and differentiation of HCC; while, Cyclin E may be a useful marker formonitoring tumor behavior. p21 and p27 can be used as predictive markers for HCC. Furthermore, higher expression of Rb/p105 as well as inverse relation with p21 and histologic grades suggests its important role in hepatic carcinogenesis.

Keywords: Chronic hepatitis C, Liver cirrhosis, Hepatocellular carcinoma, Cell cycle, Cyclin D1, Cyclin E, p21, p27, Rb/p105