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Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

Oxidative stress (OS) plays an important role in the progression of chronic liver disease and hepatocarcinogenesis. However, the role of OS in the progression of hepatocellular carcinoma (HCC) is unclear. The aim of this study was to assess whether OS promotes angiogenesis in HCC.

Methods

The expressions of vascular endothelial growth factor (VEGF), VEGF receptor2 (VEGFR2), and phosphorylated Akt were assessed, and microvessel density (MVD) and the cancer-associated fibroblast (CAF) population were examined by immunohistological staining in 55 HCC samples. The OS level in these tissues was assessed using 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2-nonenal (4-HNE) immunostaining, and an 8-OHdG enzyme-linked immunosorbent assay (ELISA). The expression and activation of angiogenic factors and the effect of growth stimulation of human umbilical vein endothelial cells (HUVECs) were also assessed in vitro, using HLE hepatoma-derived cells and conditioned medium with or without treatment with hydrogen peroxide (H2O2); a phosphoinositide 3-kinase (PI3K) inhibitor, wortmannin; and an anti-oxidative agent, N-acetyl-l-cysteine (NAC).

Results

A higher OS grade was significantly associated with higher MVD, VEGF expression, Akt activity, and OS grade of CAFs, but not with the percentage of the CAFpopulation in HCC tissues. Additionally, cancer cells constituted a major population of OS marker-positive cells in HCC tissues. In vitro, H2O2 treatment induced up-regulation of VEGF at both the mRNA and protein levels, activated Akt, and resulted in the proliferation of HUVECs; the addition of wortmannin and NAC counteracted the effects of OS.

Conclusions

OS enhances the malignant potential of HCC through the stimulation of angiogenesis by activation of the Akt-VEGF pathway.

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research ”KAKENHI” No. 19790491 from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan

    Masayasu Jo, Taichiro Nishikawa, Tomoki Nakajima, Yoshihisa Okada, Kanji Yamaguchi, Hironori Mitsuyoshi, Kohichiroh Yasui, Masahito Minami, Masaki Iwai, Keizo Kagawa, Yoshito Itoh & Toshikazu Yoshikawa

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  1. Masayasu Jo
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  2. Taichiro Nishikawa
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Correspondence to Masayasu Jo.

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Jo, M., Nishikawa, T., Nakajima, T. et al. Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma. J Gastroenterol 46, 809–821 (2011). https://doi.org/10.1007/s00535-011-0392-z

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  • DOI: https://doi.org/10.1007/s00535-011-0392-z

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