Hepatic Iron Overload Induces Hepatocellular Carcinoma in Transgenic Mice Expressing the Hepatitis C Virus Polyprotein

Furutani, Takakazu; Hino, Keisuke; Okuda, Michiari; Gondo, Toshikazu; Nishina, Sohji; Kitase, Akira; Korenaga, Masaaki; Xiao, Shu‐Yuan; Weinman, Steven A.; Lemon, Stanley M.; Sakaida, Isao; Okita, Kiwamu

doi:10.1053/j.gastro.2006.02.060

Cited by 153 publications

(151 citation statements)

References 37 publications

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“…Results correspond to the means ± SD of 6 animals. the elevation of both cyclin D1 protein and mRNA levels (Brown et al, 2006;Furutani et al, 2006). Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death.…”

Section: Ultrastructural Alterations and Autophagy In Livermentioning

confidence: 99%

Protective effects of lycopene on oxidative stress, proliferation and autophagy in iron supplementation rats

et al. 2013

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Lycopene is common in diet and known for its antioxidant activities. However, the impact of lycopene on iron metabolism is poorly investigated. In this study, we hypothesize that lycopene can prevent iron-mediated oxidative stress, proliferation and autophagy in liver and use a rat model of nutritional iron supplementation to confi rm its intervention in these defence mechanisms. We found that iron supplementation induced cell proliferation predominantly in non parenchymal cells compared with hepatocytes, but not apoptosis. In addition, iron was accumulated within the hepatic lysosomes where it triggered autophagy as evidenced by the formation of autophagic vesicles detected by LC3-B staining. Iron supplementation also induced morphologic alterations of the mitochondrial membranes probably due to increased lipid peroxidation as indicated by elevated iron and malondialdehyde concentrations in serum and tissues. Lycopene reduced iron-catalyzed lipid peroxidation by decreasing the malondialdehyde level in the liver and colon and enhancing the total superoxide dismutase activities in serum and tissues. The result suggest that lycopene prevents iron-induced oxidative stress, proliferation and autophagy at both biochemical and histological levels due to its potent free radical scavenging and antioxidant properties.

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Section: Ultrastructural Alterations and Autophagy In Livermentioning

confidence: 99%

Protective effects of lycopene on oxidative stress, proliferation and autophagy in iron supplementation rats

et al. 2013

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“…7). Next, we determined the level of 4-hydroxy-2-nonenal (HNE) protein adducts, a marker of oxidative-stress induced damage, 21 in normal liver and HCC samples by immunohistochemistry analysis. Indeed, hepatocytes with strong staining for HNE-protein adducts were easily found on tumor sections of KO but not DM mice (Fig.…”

Section: S100a8 and S100a9 Expression In Hepatocellular Carcinoma Celmentioning

confidence: 99%

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

et al. 2009

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The nuclear factor-kappaB (NF-B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-B-deficient and NF-B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)H epatocellular carcinoma (HCC) is the most frequent type of liver cancer and one of the most prevalent causes of cancer mortality worldwide. These tumors arise at sites of chronic liver injury, inflammation, and hepatocyte proliferation provoked by several causes such as chronic hepatitis B and C viral infection, chronic alcohol consumption, and aflatoxin B1-contaminated food. 1,2 Despite remarkable improvements in diagnosis, only limited therapeutic options exist, most of them with minimal clinical benefit. 2 Moreover, there is

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“…Oxidative stress induced by HCV reduces hepcidin transcription followed by ferroportin expression in enterocytes and increases duodenal iron uptake [72,76] . An excess of dietary iron fed to HCV transgenic mice induces excess hepatocarcinogenesis [77] . Iron and resultant oxidative stress closely correlate with the progress of chronic hepatitis C and related HCC development that should be incorporated as treatment options.…”

Section: Mechanisms Of Hbv-related Hcc and Oxidative Stress Involvementmentioning

confidence: 99%

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

Takaki

Yamamoto

2015

WJH

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stress, causing a high rate of hepatocarcinogenesis among patients with cirrhosis. Non-alcoholic steatohepatitis is also associated with oxidative stress although its hepatocarcinogenic potential is lower than that of chronic hepatitis C. Analyses of serum markers and histological findings have shown that hepatocellular carcinoma correlates with oxidative stress and experimental data indicate that oxidative stress increases the likelihood of developing hepatocarcinogenesis. However, the results of antioxidant therapy have not been favorable. Physiological oxidative stress is a necessary biological response, and thus adequate control of oxidative stress and a balance between oxidative and anti-oxidative responses is important. Several agents including metformin and L-carnitine can reportedly control mechanistic oxidative stress. This study reviews the importance of oxidative stress in hepatocarcinogenesis and of control strategies for the optimal survival of patients with CLD and hepatocellular carcinoma. Core tip: Oxidative stress is a key biological response that correlates with the progression of chronic liver disease. However, oxidative stress is an essential survival mechanism and thus to erase it is an unsuitable approach to disease control. As hepatocarcinogenesis is closely associated with increased oxidative stress via viral proteins or chronic inflammation and lipids, controlling oxidative stress should be effective against progressive liver disease. Agents that can control oxidative stress might represent a more effective approach than reactive oxygen species-scavenging agents. AbstractOxidative stress is becoming recognized as a key factor in the progression of chronic liver disease (CLD) and hepatocarcinogenesis. The metabolically important liver is a major reservoir of mitochondria that serve as sources of reactive oxygen species, which are apparently responsible for the initiation of necroinflammation. As a result, CLD could be a major inducer of oxidative stress. Chronic hepatitis C is a powerful generator of oxidative REVIEWSubmit a

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Hepatic Iron Overload Induces Hepatocellular Carcinoma in Transgenic Mice Expressing the Hepatitis C Virus Polyprotein

Cited by 153 publications

References 37 publications

Protective effects of lycopene on oxidative stress, proliferation and autophagy in iron supplementation rats

Protective effects of lycopene on oxidative stress, proliferation and autophagy in iron supplementation rats

S100A8 and S100A9 are novel nuclear factor kappa B target genes during malignant progression of murine and human liver carcinogenesis

Control of oxidative stress in hepatocellular carcinoma: Helpful or harmful?

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