Article

Causes of and Prevention Strategies for Hepatocellular Carcinoma

Sezione di Gastroenterologia, DIBIMIS, University of Palermo, Palermo, Italy.
Seminars in Oncology (Impact Factor: 3.94). 08/2012; 39(4):374-83. DOI: 10.1053/j.seminoncol.2012.05.006
Source: PubMed

ABSTRACT Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated with a high rate of mortality and its prevalence in the United States and in Western Europe is increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the incidence of non-alcoholic steatohepatitis-related HCC may also be expected to increase, and a potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination against HBV is the most efficient primary prevention measure currently available to reduce the HCC incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature suggests a slight preventive effect of antiviral therapy on HCC development in patients with HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.

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    ABSTRACT: Background & Aims While nonalcoholic fatty liver disease (NAFLD) is the most common risk factor of chronic liver disease, the mechanisms that initiate its development are obscure. Hepassocin (HPS) is a hepatokine that has been reported to be involved in liver regeneration. In addition to the mitogenic activity of HPS, HPS expression is decreased in patients with hepatoma. However, the role of HPS in NAFLD is still unknown. Methods A total 393 of human subjects with (n=194) or without (n=199) NAFLD were enrolled to evaluate the serum HPS concentration. In order to clarify the causal inference between HPS and NAFLD, we used experimental animal and cell models. Hepatic over-expression or silence of HPS was achieved by lentiviral vector delivery in mice and lipofectamine transfection in HepG2 cells. Lipogenesis related proteins were detected by western blots. The expression of inflammatory factors were determined by real-time polymerase chain reaction. Results Subjects with NAFLD had a higher serum HPS concentration than those without it. Overexpression of HPS increased hepatic lipid accumulation and NAFLD activity scores (NAS), whereas deletion of HPS improved high fat diet-induced hepatic steatosis and decreased NAS in mice. Additionally, oleic acid, a steatogenic reagent increased HPS expression in hepatocytes. Furthermore, overexpression of HPS in HepG2 cells induced lipid accumulation through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway, whereas deletion of HPS decreased oleic acid-induced lipid accumulation. Conclusions The present study provides evidence that HPS plays an important role in NAFLD and induces hepatic lipid accumulation through an ERK1/2-dependent pathway.
    Journal of Hepatology 06/2013; 59(5). DOI:10.1016/j.jhep.2013.06.004 · 10.40 Impact Factor
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    ABSTRACT: Due to the possible involvement of Glutathione S-transferase Mu-1 (GSTM1) and Glutathione S-transferase theta-1 (GSTT1) in the detoxification of environmental carcinogens, environmental toxins, and oxidative stress products, genetic polymorphisms of these two genes may play important roles in the susceptibility of human being to hepatocellular carcinoma. However, the existing research results are not conclusive. A systematic literature search using databases (PubMed, Scopus, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Wanfang Data, etc.) for the eligible studies meeting the inclusion criteria including case-control studies or cohort studies is evaluated using an updated systematic meta-analysis. Significant increase in the risk of HCC in the Chinese population is found in GSTM1 null genotype (OR = 1.47, 95% CI: 1.21 to 1.79, P<0.001) and GSTT1 null genotype (OR = 1.38, 95% CI: 1.14 to 1.65, P<0.001). Analysis using the random-effects model found an increased risk of HCC in GSTM1-GSTT1 dual null population (OR = 1.79, 95% CI: 1.26 to 2.53, P<0.001). In addition, subgroup analyses showed a significant increase in the association of GST genetic polymorphisms (GSTM1, GSTT1, and GSTM1-GSTT1) with HCC in southeast and central China mainland. However, available data collected by this study fail to show an association between GST genetic polymorphisms and HCC in people from the Taiwan region (for GSTM1: OR = 0.78, 95% CI: 0.60 to 1.01, P = 0.06; for GSTT1: OR = 0.94, 95% CI: 0.78 to 1.14, P = 0.546; for GSTM1-GSTT1: OR = 1.04, 95% CI: 0.81 to 1.32, P = 0.77). Sensitivity analysis and publication bias diagnostics confirmed the reliability and stability of this meta-analysis. Our results indicate that both GSTM1 and GSTT1 null genotypes are associated with an increased HCC risk in Chinese population. Peoples with dual null genotypes of GSTM1-GSTT1 are more susceptible to developing HCC. In conclusion, GST genetic polymorphisms play vital roles in the development of HCC in the Chinese population.
    PLoS ONE 02/2013; 8(2):e57043. DOI:10.1371/journal.pone.0057043 · 3.53 Impact Factor

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