Potential role of bcl-2 and bax mRNA and protein expression in chronic hepatitis type B and C: a clinicopathologic study.
Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli. In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18-13/18, and the fibrosis Stage, from 1-6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5-6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages. In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P <.001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1-5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells. Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.
Tsamandas
Athanassios C
AC
Departments of Pathology, University of Patras School of Medicine, Patras, Greece. tsamanda@otenet.gr
Thomopoulos
Konstantinos
K
Zolota
Vassiliki
V
Kourelis
Theodore
T
Karatzas
Theodore
T
Ravazoula
Panagiota
P
Tepetes
Konstantinos
K
Petsas
Theodore
T
Karavias
Dionissios
D
Karatza
Chrisoula
C
Bonikos
Dionysis S
DS
Gogos
Charalambos
C
D000328:Adult; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D005260:Female; D015870:Gene Expression; D019694:Hepatitis B, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein