Hepatitis: Rosenbaum J

Zucman-Rossi J, Clément B, Buendia MA, Lerat H, Beers BV, Bedossa P, Taieb J, Rosenbaum J. · Inserm, U674 ; université Paris-Diderot-Paris-VII, 75010 Paris, France. · Bull Cancer. · Pubmed #19211359 No free full text.

Abstract: Hepatocellular carcinogenesis is usually the result of a muti-step process. It begins with an exposure to various risk factors; followed by the development of a chronic hepatitis and cirrhosis that is a pre-neoplastic step; and finally after the occurrence of an hepatocellular carcinoma (HCC), different molecular events control aggressiveness of the tumors. The aim of this work was to identify in the international context, forces and priorities of the fundamental and translational HCC research.

Blanc JF, Lalanne C, Plomion C, Schmitter JM, Bathany K, Gion JM, Bioulac-Sage P, Balabaud C, Bonneu M, Rosenbaum J. · INSERM, E362, IFR66 Bordeaux, Université Victor Segalen Bordeaux 2, Bordeaux, France. · Proteomics. · Pubmed #16097030 No free full text.

Abstract: Hepatocellular carcinoma (HCC) is a major complication of chronic viral hepatitis C. Therapy for HCC is still disappointing. It is thus of great importance to identify novel HCC markers for early detection of the disease, and tumor-specific proteins as potential therapeutic targets. We have used a proteomic approach to identify new proteins involved in HCC development. Four cases of HCC developing from chronic viral hepatitis C were analyzed by two-dimensional electrophoresis (2-DE), and results were compared to those of paired adjacent non-tumorous liver tissues. For MS fingerprinting, protein spots with differential intensity between HCC and non-tumorous liver were directly cut out of gels and processed for MALDI-MS and nano-LC-ESI-MS/MS analysis. Approximately 850 spots were visualized in each gel. The comparative analysis of paired samples indicated that 345 protein spots showed significant differences in expression level between non-tumor and tumor tissue. Among the 345 protein spots analyzed, 238 spots corresponding to 155 different proteins were identified; 49 proteins were up-regulated, whereas 106 proteins were down-regulated. Among these 155 proteins, 91 proteins were regulated in at least three cases. Although 52 out of these 91 proteins have been already described by previous proteomic or transcriptomic studies, or are already known to be involved in hepatocarcinogenesis, this experiment revealed 39 new proteins differentially expressed in HCC developing from viral hepatitis C. Variations in protein accumulation were confirmed for two selected proteins (apolipoprotein E, chloride intracellular channel 1) by Western blotting in ten additional cases of HCC developing in patients with viral hepatitis C.

Tan K, Guibert C, Neaud V, Rosenbaum J. · Groupe de Recherches pour l'Etude du Foie, INSERM E 0362 and IFR 66, Université Victor Segalen Bordeaux 2, Bordeaux, France. · J Viral Hepat. · Pubmed #14633175 No free full text.

Abstract: Although liver fibrosis is the major complication of hepatitis C virus (HCV) infection, the mechanisms of fibrogenesis in this setting are not completely understood. The aim of this study was to test the direct effect of HCV proteins on signalling- and fibrosis-related events in cultured human liver myofibroblasts, the effector cells of liver fibrogenesis. Cultured myofibroblasts were exposed to recombinant HCV core, a structural protein, and nonstructural proteins (NS) 3, NS 4 and NS 5. HCV proteins did not significantly increase DNA synthesis in myofibroblasts. We then examined if these proteins affected early signalling events. None of the HCV proteins affected the phosphorylation of the mitogen activated protein kinases/extracellular regulated kinases 1 and 2, or of the phosphatidylinositol 3-kinase target, Akt. HCV proteins had also no effect on intracellular calcium concentration. In other experiments, fibrogenesis-related parameters were measured. None of the HCV proteins had any effect on the secretion of type I collagen, tissue inhibitor of matrix metalloproteinases type 1, gelatinase or urokinase. Alpha-smooth muscle actin expression was also not modified. In summary, our experiments do not support a direct effect of these HCV proteins on fibrogenic cells.

Rullier A, Trimoulet P, Urbaniak R, Winnock M, Zauli D, Ballardini G, Rosenbaum J, Balabaud C, Bioulac-Sage P, Le Bail B. · Service d'Anatomie Pathologique, Hôpital Pellegrin, Bordeause, France. · Mod Pathol. · Pubmed #11353061 links to  free full text

Abstract: Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process. Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR. A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC. These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.

Le Bail B, Faouzi S, Boussarie L, Guirouilh J, Blanc JF, Carles J, Bioulac-Sage P, Balabaud C, Rosenbaum J. · Groupe de Recherches pour l'Etude du Foie and Laboratoire de Pathologie, Université Victor Ségalen Bordeaux 2, Bordeaux, France. · J Pathol. · Pubmed #10451487 No free full text.

Abstract: Osteonectin (ON)/SPARC is a glycoprotein involved in extracellular matrix remodelling. ON expression by myofibroblasts has been reported in fibrotic human liver. As ON also plays a role in cell adhesion, differentiation, and proliferation, this study was designed to document its expression in human hepatocellular carcinoma (HCC). Tissues from 26 HCCs of various histological grades and architecture and from surrounding non-tumour liver (23 cirrhotic or fibrotic, three non-fibrotic) were tested by in situ hybridization and immunohistochemistry. Immunohistochemical detection of alpha-smooth muscle actin (alpha-SMA) was performed on serial sections or in combination with hybridization. Large amounts of ON mRNA and protein were detected in the tumour capsule, in the fibrous bands, and along capillaries within HCCs. The signal was located in cells suggestive of myofibroblasts, as confirmed by positive staining for alpha-SMA. In HCC, ON protein was always detectable, with strong staining in high-grade tumours, whereas it was mostly undetectable in non-tumour tissues. A clear difference was also shown for ON transcripts, except in a few cases with chronic active hepatitis, where ON transcripts were also expressed at a high level. Overexpression of ON transcripts in HCC vs. non-tumour liver was confirmed by RNA blot in 20/22 patients tested. In conclusion, ON is strongly expressed by the stromal myofibroblasts of human HCC, especially of high grade. This expression could play a role in tumour progression.