Molecular targets and oxidative stress biomarkers in hepatocellular carcinoma: An overview

Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
Journal of Translational Medicine (Impact Factor: 3.93). 10/2011; 9(1):171. DOI: 10.1186/1479-5876-9-171
Source: PubMed


Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple genetic aberrations. Several molecular pathways involved in the regulation of proliferation and cell death are implicated in the hepatocarcinogenesis. The major etiological factors for HCC are both hepatitis B virus (HBV) and hepatitis C virus infection (HCV).
Continuous oxidative stress, which results from the generation of reactive oxygen species (ROS) by environmental factors or cellular mitochondrial dysfunction, has recently been associated with hepatocarcinogenesis. On the other hand, a distinctive pathological hallmark of HCC is a dramatic down-regulation of oxido-reductive enzymes that constitute the most important free radical scavenger systems represented by catalase, superoxide dismutase and glutathione peroxidase.
The multikinase inhibitor sorafenib represents the most promising target agent that has undergone extensive investigation up to phase III clinical trials in patients with advanced HCC. The combination with other target-based agents could potentiate the clinical benefits obtained by sorafenib alone. In fact, a phase II multicenter study has demonstrated that the combination between sorafenib and octreotide LAR (So.LAR protocol) was active and well tolerated in advanced HCC patients.
The detection of molecular factors predictive of response to anti-cancer agents such as sorafenib and the identification of mechanisms of resistance to anti-cancer agents may probably represent the direction to improve the treatment of HCC.

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Available from: Paola Stiuso
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    • "At high ROS level, however, ROS causes oxidative stress and a toxic environment to the cells [13]. This stressful condition is known to play a major role in HCC mainly by enhancing DNA damage and by modifying some key cellular process for development [13]. Virus-induced ROS have an effect not only on infected cells but also on the virus itself. "
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    ABSTRACT: Hepatitis B virus (HBV) infection induces reactive oxygen species (ROS) production and has been associated with the development of hepatocellular carcinoma (HCC). ROS are also an important factor in HCC because the accumulated ROS leads to abnormal cell proliferation and chromosome mutation. In oxidative stress, heat shock protein 90 (Hsp90) and glutathione (GSH) function as part of the defense mechanism. Hsp90 prevents cellular component from oxidative stress, and GSH acts as antioxidants scavenging ROS in the cell. However, it is not known whether molecules regulated by oxidative stress are involved in HBV capsid assembly. Based on the previous study that Hsp90 facilitates HBV capsid assembly, which is an important step for the packing of viral particles, here, we show that ROS enrich Hsp90-driven HBV capsid formation. In cell-free system, HBV capsid assembly was facilitated by ROS with Hsp90, whereas it was decreased without Hsp90. In addition, GSH inhibited the function of Hsp90 to decrease HBV capsid assembly. Consistent with the result of cell-free system, ROS and buthionine sulfoximine (BS), an inhibitor of GSH synthesis, increased HBV capsid formation in HepG2.2.15 cells. Thus, our study uncovers the interplay between ROS and Hsp90 during HBV capsid assembly. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jan 2015 · Biochemical and Biophysical Research Communications
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    • "Oxidative stress has been hypothesised to contribute to the aetiology of liver cancer and liver disease (Ha et al, 2010). For example, both HBV and HCV have been suggested to enrich inflammatory and oxidative conditions in hepatocytes (Marra et al, 2011). In addition, obesity and diabetes are also thought to promote inflammation and the formation of reactive oxygen species (Hopps et al, 2010; Pitocco et al, 2010; Powell et al, 2010). "
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    ABSTRACT: Background: Micronutrients may influence the development or progression of liver cancer and liver disease. We evaluated the association of serum α-tocopherol, β-carotene, and retinol with incident liver cancer and chronic liver disease (CLD) mortality in a prospective cohort of middle-aged Finnish male smokers. Methods: Baseline and 3-year follow-up serum were available from 29,046 and 22,805 men, respectively. After 24 years of follow-up, 208 men were diagnosed with liver cancer and 237 died from CLD. Hazards ratios and 95% confidence intervals were calculated for highest vs lowest quartiles from multivariate proportional hazards models. Results: Higher β-carotene and retinol levels were associated with less liver cancer (β-carotene: 0.35, 0.22-0.55, P-trend <0.0001; retinol: 0.58, 0.39-0.85, P-trend=0.0009) and CLD mortality (β-carotene: 0.47, 0.30-0.75, P-trend=0.001; retinol: 0.55, 0.38-0.78, P-trend=0.0007). α-Tocopherol was associated with CLD mortality (0.63, 0.40-0.99, P-trend=0.06), but not with liver cancer (1.06, 0.64-1.74, P-trend=0.77). Participants with higher levels of β-carotene and retinol, but not α-tocopherol, at both baseline and year 3 had lower risk of each outcome than those with lower levels. Conclusions: Our findings suggest that higher concentrations of β-carotene and retinol are associated with incident liver cancer and CLD. However, such data do not indicate that supplementation should be considered for these diseases.
    Full-text · Article · Oct 2014 · British Journal of Cancer
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    • "This clearly indicates that detecting the HCC at earlier stage can significantly benefit the HCC patients. In recent years, although a wide range of molecular biomarkers, including Glypican-3 [25], GP73 [26], and other oxidative stress related biomarkers [27], have been developed, most of them lack adequate functional significance with HCC. Thus, how those findings could be applied in daily clinical practice remains unknown. "
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    ABSTRACT: In recent years, high throughput technologies such as microarray platform have provided a new avenue for hepatocellular carcinoma (HCC) investigation. Traditionally, gene sets enrichment analysis of survival related genes is commonly used to reveal the underlying functional mechanisms. However, this approach usually produces too many candidate genes and cannot discover detailed signaling transduction cascades, which greatly limits their clinical application such as biomarker development. In this study, we have proposed a network biology approach to discover novel biomarkers from multidimensional omics data. This approach effectively combines clinical survival data with topological characteristics of human protein interaction networks and patients expression profiling data. It can produce novel network based biomarkers together with biological understanding of molecular mechanism. We have analyzed eighty HCC expression profiling arrays and identified that extracellular matrix and programmed cell death are the main themes related to HCC progression. Compared with traditional enrichment analysis, this approach can provide concrete and testable hypothesis on functional mechanism. Furthermore, the identified subnetworks can potentially be used as suitable targets for therapeutic intervention in HCC.
    Full-text · Article · May 2014 · BioMed Research International
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