Related Experiment Videos
Activation of ras oncogene in livers with cirrhosis
P Liu1, J F Fléjou, G Feldmann
1Laboratoire de Biologie Cellulaire, INSERM U 327, Faculté de Médecine Xavier-Bichat, Université Paris VII Denis Diderot, France.
Abstract:
Activation of cellular oncogenes and inactivation of anti-oncogenes have been postulated as important mechanisms during hepatocarcinogenesis. This study was conducted to detect abnormal levels of several proto-oncogenes (c-jun, c-fos, c-H-ras) and of the p53 and the alpha-fetoprotein gene in the liver during cirrhosis, a pathological process which predisposes to the development of hepatocarcinoma. Liver tissue from 11 patients with cirrhosis of different etiologies, and seven histologically normal liver fragments taken at the periphery of benign liver tumors of metastases were studied. Transcripts of the various oncogenes and of the alpha-fetoprotein gene were detected by in situ hybridization, and the p53 protein was revealed by immunocytochemistry. No overexpression of any of the mRNA tested or of the p53 protein was found in histologically normal liver in contact with benign or metastatic tumors. In contrast, 10 of the 11 specimens with cirrhosis (90.9%) displayed abnormally high levels of c-H-ras transcripts. Five samples with cirrhosis revealed a moderate increase in the level of c-fos mRNA. Only one case and two cases, respectively, exhibited increased levels of c-jun and alpha-fetoprotein mRNA. No cases were positive for the p53 antigen. Liver-cell proliferation, as assessed by immunocytochemistry with the Ki 67 monoclonal antibody, was low in both the group with cirrhosis and the control groups (0.49% and 0.55% positive cells, respectively). These data demonstrate that activation of c-H-ras mRNA is an almost constant finding in hepatocytes of livers with cirrhosis. This gene overexpression is not linked to hepatocellular proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Hepatocellular carcinoma (HCC) risk increases with cirrhosis. This study found high c-H-ras oncogene activation in most cirrhosis liver samples, suggesting its role in hepatocarcinogenesis independent of cell proliferation.
Area of Science:
- Hepatology
- Oncology
- Molecular Biology
Background:
- Cirrhosis is a major risk factor for hepatocellular carcinoma (HCC).
- Oncogene activation and tumor suppressor gene inactivation are key mechanisms in hepatocarcinogenesis.
- Proto-oncogenes (c-jun, c-fos, c-H-ras), p53, and alpha-fetoprotein gene expression in cirrhosis require further investigation.
Purpose of the Study:
- To investigate the expression of proto-oncogenes (c-jun, c-fos, c-H-ras), p53, and alpha-fetoprotein in cirrhotic liver tissue.
- To determine if oncogene abnormalities correlate with cirrhosis and the risk of developing HCC.
- To assess the relationship between oncogene expression and hepatocellular proliferation.
Main Methods:
- In situ hybridization was used to detect mRNA transcripts of oncogenes and alpha-fetoprotein.
- Immunocytochemistry was employed to detect p53 protein and Ki 67 for cell proliferation.
- Liver tissue samples from 11 cirrhosis patients and 7 normal controls were analyzed.
Main Results:
- Abnormally high levels of c-H-ras transcripts were observed in 90.9% of cirrhosis specimens.
- Moderate increases in c-fos mRNA were found in 5 samples.
- Increased c-jun and alpha-fetoprotein mRNA were detected in only a few cases; p53 protein was not detected. No oncogene overexpression or p53 was found in normal liver tissue.
- Hepatocellular proliferation was low and similar in both cirrhotic and control groups.
Conclusions:
- Activation of c-H-ras mRNA is a frequent finding in hepatocytes of cirrhotic livers.
- This c-H-ras gene overexpression in cirrhosis is not associated with increased hepatocellular proliferation.
- The findings suggest a significant role for c-H-ras activation in the early stages of hepatocarcinogenesis during cirrhosis.