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Susceptibilité génétique des variants EP300 et PCAF au carcinome hépatocellulaire et rôle de septine 9, PIAS1 et SUMO1 dans la réplication du virus de l'hépatite C

Abstract : Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer worldwide and the third most common cause of cancer mortality. HCC is one of the few cancers with welldefined major risk factors. Major causes of HCC include hepatitis B, hepatitis C, alcoholic liver disease, nonalcoholic, steatohepatitis, hereditary hemochromatosis, and geneticalteration. The multifactorial causes of HCC might explain its complex molecular pathogenesis. Detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve our current concepts for screening and treatment of this disease. With a view toward current concepts for screening of this disease, first, we analyzed a genetic susceptibility to hepatocellular carcinoma. The aim of the current study was to assess the impact of the Ile997Val in EP300 and Asn386Ser in PCAF polymorphisms on the risk of HCC. we found that the Val/Val of the EP300 at codon 997 and Ser/Ser of the PCAF at codon 386 were associated with an increased risk of HCC in the Moroccan population. A higher risk of HCC was observed in HCV-negative subjects. We also found that male with Ser/Ser in thePCAF gene and women with Val/Val genotype of the EP300 had a higher risk to develop HCC. It appears that variants of the transcriptional coactivator genes (EP300 and PCAF) may influence HCC risk in populations with low mutations or hromosomal instability rates. Additional surveys are warranted to confirm this first report. The incidence of HCC is increasing in Western countries, mostly because of the high prevalence of hepatitis C virus (HCV) infection. In this sense, we have tried to identify new host factors involved in replication of HCV. Hepatitis C virus (HCV) replicates in the liver,and chronic infection often leads to cirrhosis, steatosis, and hepatocellular carcinoma. There is no vaccine to protect against HCV infection. Major improvement has been recently achieved regarding treatment of HCV infection however there is already evidence for emergence of resistance due to the high genetic variability of the HCV RNA genome. Thus it should be important, to design therapies which avoid genotypic resistance by targeting cellular proteins. Understanding the mechanisms that allow proper assembly and intracellular trafficking of HCV proteins may have a profound impact on the treatment efficacy. An important hallmark of chronic HCV infection is liver steatosis associated with the accumulation of lipid droplets (LDs). The LDs accumulated in the HCV infected cells and the HCV core protein induces the redistribution of LDs, through the clustering of these organelles in the perinuclear area, providing a platform for virus assembly and in the production of infectious particles. Several host proteins have been proposed to facilitate the replication of HCV however much is needed to elucidate the implicated mechanisms. Here we report that HCV infection increases expression and formation of septin 9 filament surrounding HCV core. Data of our study revealed the highest expression of septin 9 in samples from hepatocellular carcinoma (HCC) from patients with chronic HCV infection. Indeed, we brought newperception of septin 9 function regarding both microtubule and lipid structure organization. We proposed that HCV infection conducts to assembly of septin 9 in filaments through PIAS1. This may provide scaffolds to organize the microtubules network and LDs redistribution required for HCV assembly and replication. This study illuminates a new function of septin 9 in HCV life cycle through its association with lipids and microtubules. These events might depend on septin 9 SUMO1 modification by PIAS1. These findings also provide a step forwards in understanding the relationship between HCV and its host and open new therapeutic directions.
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Abdellah Akil. Susceptibilité génétique des variants EP300 et PCAF au carcinome hépatocellulaire et rôle de septine 9, PIAS1 et SUMO1 dans la réplication du virus de l'hépatite C. Médecine humaine et pathologie. Université Paris Sud - Paris XI; Université Mohammed V (Rabat), 2012. Français. ⟨NNT : 2012PA11T079⟩. ⟨tel-01083259⟩

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