The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations...The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations,genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci,nodules,and finally,overt HCC.As well as many other neoplasias,liver cancer is considered an"inflammatory cancer",arising from a context of inflammation,and characterized by inflammation-related mechanisms that favor tumor cell survival,proliferation,and invasion.Molecular mechanisms that link inflammation and neoplasia have been widely investigated,and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species.The latter,in turn,probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation,and ultimately leading to cancer.The relationship amongst chronic liver injury,free radical production,and development of HCC is explored in the present review,particularly in the light of the complex network that involves oxidative DNA damage,cytokine synthesis,telomere dysfunction,and microRNA regulation.展开更多
AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37...AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TIMF-α, IL-1β, TGF-αand c-myc in liver specimens was detected by semi-quantitative comparative RT-PCR. RESULTS: TNF-αlevels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1βwas higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-αand staging (P=0.05) and between IL-1βlevels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-αexpression and HCV genotype (P=0.02). CONCLUSION: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-αlevels. As HCV-related liver damage progresses, TNF-αlevels drop while IL-1βand c-myc levels increase, which may be relevant to liver carcinogenesis.展开更多
文摘The histo-pathologic and molecular mechanisms leading to initiation and progression of hepatocellular carcinoma(HCC)are still ill-defined;however,there is increasing evidence that the gradual accumulation of mutations,genetic and epigenetic changes which occur in preneoplastic hepatocytes results in the development of dysplastic foci,nodules,and finally,overt HCC.As well as many other neoplasias,liver cancer is considered an"inflammatory cancer",arising from a context of inflammation,and characterized by inflammation-related mechanisms that favor tumor cell survival,proliferation,and invasion.Molecular mechanisms that link inflammation and neoplasia have been widely investigated,and it has been well established that inflammatory cells recruited at these sites with ongoing inflammatory activity release chemokines that enhance the production of reactive oxygen species.The latter,in turn,probably have a major pathogenic role in the continuum starting from hepatitis followed by chronic inflammation,and ultimately leading to cancer.The relationship amongst chronic liver injury,free radical production,and development of HCC is explored in the present review,particularly in the light of the complex network that involves oxidative DNA damage,cytokine synthesis,telomere dysfunction,and microRNA regulation.
基金Supported by PRIN grants from the Italian Ministry of Science and Technology, No. 2003063143-006
文摘AIM: To assess whether a correlation exists between oxidative DNA damage occurring in chronic HCV-related hepatitis and expression levels of pro-inflammatory cytokines, TGF-αand c-myc. METHODS: The series included 37 patients with chronic active HCV-related hepatitis and 11 with HCV-related compensated cirrhosis. Eight-hydroxydeoxyguanosine in liver biopsies was quantified using an electrochemical detector. The mRNA expression of TIMF-α, IL-1β, TGF-αand c-myc in liver specimens was detected by semi-quantitative comparative RT-PCR. RESULTS: TNF-αlevels were significantly higher in hepatitis patients than in cirrhosis patients (P=0.05). IL-1βwas higher in cirrhosis patients (P=0.05). A significant correlation was found between TNF-αand staging (P=0.05) and between IL-1βlevels and grading (P=0.04). c-myc showed a significantly higher expression in cirrhosis patients (P=0.001). Eight-hydroxydeoxyguanosine levels were significantly higher in cirrhosis patients (P=0.05) and in HCV genotype 1 (P=0.03). Considering all patients, 8-hydroxydeoxyguanosine levels were found to be correlated with genotype (P=0.04) and grading (P=0.007). Also multiple logistic regression analysis demonstrated a significant correlation among the number of DNA adducts, TNF-αexpression and HCV genotype (P=0.02). CONCLUSION: In chronic HCV-related liver damage, oxidative DNA damage correlates with HCV genotype, grading and TNF-αlevels. As HCV-related liver damage progresses, TNF-αlevels drop while IL-1βand c-myc levels increase, which may be relevant to liver carcinogenesis.
