caa a22 4500 445887818 CHVBK 20180317145605.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00535-011-0392-z doi (NATIONALLICENCE)springer-10.1007/s00535-011-0392-z Oxidative stress is closely associated with tumor angiogenesis of hepatocellular carcinoma [Elektronische Daten] [Masayasu Jo, Taichiro Nishikawa, Tomoki Nakajima, Yoshihisa Okada, Kanji Yamaguchi, Hironori Mitsuyoshi, Kohichiroh Yasui, Masahito Minami, Masaki Iwai, Keizo Kagawa, Yoshito Itoh, Toshikazu Yoshikawa] 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. Springer, 2011 Hepatocellular carcinoma nationallicence Angiogenesis nationallicence Oxidative stress nationallicence Vascular endothelial growth factor nationallicence Akt nationallicence Jo Masayasu Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Nishikawa Taichiro Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Nakajima Tomoki Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Okada Yoshihisa Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Yamaguchi Kanji Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Mitsuyoshi Hironori Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Yasui Kohichiroh Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Minami Masahito Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Iwai Masaki Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Kagawa Keizo Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Itoh Yoshito Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Yoshikawa Toshikazu Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut Journal of Gastroenterology Springer Japan 46/6(2011-06-01), 809-821 0944-1174 46:6<809 2011 46 535 https://doi.org/10.1007/s00535-011-0392-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00535-011-0392-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Jo Masayasu Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Nishikawa Taichiro Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Nakajima Tomoki Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Okada Yoshihisa Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Yamaguchi Kanji Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Mitsuyoshi Hironori Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Yasui Kohichiroh Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Minami Masahito Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Iwai Masaki Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Kagawa Keizo Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Itoh Yoshito Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 700 1- Yoshikawa Toshikazu Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan aut NATIONALLICENCE 773 0- Journal of Gastroenterology Springer Japan 46/6(2011-06-01), 809-821 0944-1174 46:6<809 2011 46 535 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer