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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    • "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.
    Biochemical and Biophysical Research Communications 01/2015; 457(3). DOI:10.1016/j.bbrc.2014.12.110 · 2.30 Impact Factor
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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.
    BioMed Research International 05/2014; 2014:278956. DOI:10.1155/2014/278956 · 1.58 Impact Factor
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    • "Because the liver is infiltrated with byproducts of fatty acid oxidation and because altered handling of hepatic oxidation products is associated with liver damage and disease [5], the inappropriate programming of this crucial protective mechanism by a maternal HF diet may be deleterious for hepatic development and health. Additionally, because hepatic oxidative balance is often related to systemic antioxidant status [6] [7] [8], the altered production of these in the liver will likely have numerous consequences for all major organ systems. The paraoxonase (PON) family of enzymes is critical for wholesystem oxidative balance [9]. "
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    ABSTRACT: The antioxidant (AOX) defense system is critical for combating whole-body oxidative stress, and the present study aimed to determine the consequences of a maternal high-fat (HF) diet on neonatal hepatic lipid accumulation, oxidative stress, the expression of AOX genes, as well as epigenetic histone modifications within Pon1, an AOX enzyme. Hepatic thiobarbituric acid reactive substances were significantly increased and nonesterified fatty acids decreased in offspring of HF-fed dams, while triglycerides increased in male but not female HF offspring when compared to controls (C). Pon1, Pon2, Pon3 and Sod2 were significantly increased in offspring of HF-fed dams when compared to C. However, the increase in Pon1 and Pon3 was only significant in male but not female offspring. When compared to C, the hepatic Pon1 promoter of male and female HF offspring had significantly more acetylated histone H4 as well as dimethylated histone H3 at lysine residue 4, which are both involved in transcriptional activation. Trimethylation of histone H3 at lysine residue 9, which is involved in transcriptional repression, was only associated with genes in females. Results from the present study reveal that a maternal HF diet affects hepatic metabolism in the neonate in a gender-specific manner, and these differences, in association with epigenetic modification of histones, may contribute to the known gender differences in oxidative balance.
    The Journal of nutritional biochemistry 02/2014; 25(2):170-6. DOI:10.1016/j.jnutbio.2013.09.016 · 3.79 Impact Factor
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