Chronic hepatitis B virus (HBV) carriers may develop hepatocellular carcinoma (HCC) by a wide range of mechanisms including angiogenesis. We show that HBV replication induces the expression of angiogenic proteins interleukin 6 (IL6) and cyclooxygenase-2 (Cox2). Interestingly, ibuprofen (a Cox2 inhibitor) is found to attenuate the levels of IL6 and Cox 2 which are induced by HBV replication.
The mechanism of attenuation of angiogenic proteins by ibuprofen was further investigated. Our results show that HBx is involved in the increase of the expression of Cox2 through the NFκB pathway. However, the expression of Cox2 is decreased when the HBx-expressing cells are incubated with ibuprofen. The contrasting effect of HBx on Cox2 is found to be determined by differential dimer formation among the members of the NFκB family of proteins, including NFκB, RelA, and C-rel. Specifically, HBx alone results in dimer formation between NFκB and RelA, while the combined presence of HBx and ibuprofen leads to the formation of NFκB and C-rel. Additional information on the interaction network involving HBx, ibuprofen, and NFκB pathways is revealed by two-dimensional liquid chromatography-tandem mass spectrometry proteomics analysis. Taken together, our findings provide new insights on the angiogenesis induced by HBV replication.
Authors:Gamal Badra, Mahmoud Lotfy, Amany El-Refaie, Moanis Obada, Elhamy Abdelmonem, Samia Kandeel, and Amr Fathy
Liver fibrosis (LF), where the chronic HCV infection is a major cause, is a characteristic of chronic liver diseases. LF results from chronic damage to the liver in conjunction with the accumulation of ECM proteins. Matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) are thought to play an essential role in the hepatic lesions. The available data concerning the circulating levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chronic hepatitis C are not conclusive. Therefore, the present study was designed to seek the relationship between serum MMP-9, and TIMP-1 to liver status in chronic liver disease in fifty patients divided into three groups (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). MMP-9 and TIMP-1 were analyzed by the enzyme linked immunosorbent assay (ELISA). The results showed that the lowest serum level of MMP-9 was found in chronic hepatitis patients compared to the control (
< 0.05). Serum MMP-9 is decreasing during progression of chronic hepatitis to cirrhosis showing the least level in the cirrhotic group. Serum TIMP-1 was significantly higher in the cirrhotic group compared to chronic hepatitis (
< 0.05) and controls (
< 0.001). MMP-9 was negatively correlated to both TIMP-1 and the histological severity in chronic hepatitis. There was a positive correlation between TIMP-1 and the degree of fibrosis (r = 0.73,
< 0.001). Lastly, there was a statistically significant increase of MMP-9 (
< 0.001) and TIMP-1 (
< 0.05) in HCC patients compared with the other groups. In conclusion, these findings raise the possibility of using serum TIMP-1 as a non-invasive assay in liver fibrosis. Further, the altered balance between circulating MMP-9 and TIMP-1 during HCV infection may play an important role in aggravating liver injury progression in chronic liver diseases.
Authors:Pankaj Jain, Ramesh Roop Rai, Harsh Udawat, Sandeep Nijhawan, and Amit Mathur
Radhika, N. S., Duseja, A., Rajwanshi, A. et al.:
Clinico-cytopathological spectrum of HCC, its correlation with serum alpha-fetoprotein level, and hepatitis B and C viral markers. Trop. Gastroenterol., 2004,