Significance of Akt phosphorylation on tumor growth and vascular endothelial growth factor expression in human gastric carcinoma

被引:57
|
作者
Kobayashi, Iwao
Semba, Shuho
Matsuda, Yoshiko
Kuroda, Yoshikazu
Yokozaki, Hiroshi
机构
[1] Kobe Univ, Grad Sch Med, Div Surg Pathol, Dept Biomed Informat,Chuo Ku, Kobe, Hyogo 6500017, Japan
[2] Kobe Univ, Grad Sch Med, Div Gastroenterol Surg, Dept Clin & Mol Med, Kobe, Hyogo 6500017, Japan
关键词
Akt; gastric cancer; HIF-1; alpha; hypoxia; LY294002; phosphatidylinositol 3-OH kinase; vascular endothelial growth factor;
D O I
10.1159/000093087
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Objective: Hypoxia is known to be a prevalent stress stimulus and increases the transcription of vascular endothelial growth factor (VEGF) mediated by hypoxia inducible factor-1 alpha (HIF-1 alpha). We investigated the role of phosphatidyl inositol-3 OH kinase (PI3K)-Akt signaling in the regulation of HIF-1 alpha and VEGF expression in human gastric adenocarcinoma. Methods: The growth-inhibitory and apoptosis-inducing effects of the LY294002 PI3K inhibitor were analyzed in four gastric cancer cell lines and in vivo. The regulatory mechanism of VEGF and HIF-1 alpha expression under hypoxic conditions was examined in the cell cultures. In 88 gastric cancer tissue samples, phosphorylated Akt and VEGF expression were analyzed immunohistochemically. Results: LY294002 suppressed cell proliferation but induced apoptosis with decreased levels of phosphorylated Akt. HIF-1 alpha expression and VEGF secretion were induced under hypoxic conditions and VEGF protein secretion was significantly decreased by treatment with LY294002. In tumor samples, phosphorylated Akt expression was detected in 57% of the tumors, which was correlated with high VEGF expression, angiogenesis, clinicopathological parameters as well as a poor outcome. Conclusions: These findings suggest that phosphorylated Akt (Ser473) reflects the grade of malignancy in human gastric adenocarcinomas, not only in terms of tumor growth but also with respect to tumor angiogenesis. Copyright (c) 2006 S. Karger AG, Basel.
引用
收藏
页码:8 / 17
页数:10
相关论文
共 50 条
  • [1] Prognostic significance of expression of thymidine phosphorylase and vascular endothelial growth factor in human gastric carcinoma
    Kimura, H
    Konishi, K
    Nukui, T
    Kaji, M
    Maeda, K
    Yabushita, K
    Tsuji, M
    Miwa, A
    JOURNAL OF SURGICAL ONCOLOGY, 2001, 76 (01) : 31 - 36
  • [2] Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma
    Hai Shi Jian-Ming Xu Nai-Zhong Hu Hui-Jun Xie Department of Gastroenterology
    World Journal of Gastroenterology, 2003, 9 (07) : 1421 - 1426
  • [3] Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma
    Shi, H
    Xu, JM
    Hu, NZ
    Xie, HJ
    WORLD JOURNAL OF GASTROENTEROLOGY, 2003, 9 (07) : 1421 - 1426
  • [4] Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma
    Shen, GH
    Ghazizadeh, M
    Kawanami, O
    Shimizu, H
    Jin, E
    Araki, T
    Sugisaki, Y
    BRITISH JOURNAL OF CANCER, 2000, 83 (02) : 196 - 203
  • [5] Prognostic significance of vascular endothelial growth factor expression in human ovarian carcinoma
    Shen G.H.
    Ghazizadeh M.
    Kawanami O.
    Shimizu H.
    Jin E.
    Araki T.
    Sugisaki Y.
    British Journal of Cancer, 2000, 83 (2) : 196 - 203
  • [6] Pathobiological significance of vascular endothelial growth factor and Maspin expressions in human gastric carcinoma
    Li, Jian-Jun
    Chen, Ying
    Zhang, Su-Min
    Wu, Dong-Ying
    Wang, Yan-Ping
    Xin, Yan
    WORLD JOURNAL OF GASTROENTEROLOGY, 2004, 10 (18) : 2624 - 2627
  • [7] Pathobiological significance of vascular endothelial growth factor and Maspin expressions in human gastric carcinoma
    Jian-Jun Li Su-Min Zhang Dong-Ying Wu Yan-Ping Wang Yan Xin No.4 Laboratory
    World Journal of Gastroenterology, 2004, (18) : 2624 - 2627
  • [8] Prognostic Significance of Vascular Endothelial Growth Factor D in Gastric Carcinoma
    Atsuo Shida
    Shuichi Fujioka
    Yoshio Ishibashi
    Katsutoshi Kobayashi
    Hiroshi Nimura
    Norio Mitsumori
    Yutaka Suzuki
    Makio Kawakami
    Mitsuyoshi Urashima
    Katsuhiko Yanaga
    World Journal of Surgery, 2005, 29 : 1600 - 1607
  • [9] Prognostic significance of vascular endothelial growth factor D in gastric carcinoma
    Shida, A
    Fujioka, S
    Ishibashi, Y
    Kobayashi, K
    Nimura, H
    Mitsumori, N
    Suzuki, Y
    Kawakami, M
    Urashima, M
    Yanaga, K
    WORLD JOURNAL OF SURGERY, 2005, 29 (12) : 1600 - 1607
  • [10] Expression and functional significance of vascular endothelial growth factor receptors in human tumor cells
    Herold-Mende, C
    Steiner, HH
    Andl, T
    Riede, D
    Buttler, A
    Reisser, C
    Fusenig, NE
    Mueller, MM
    LABORATORY INVESTIGATION, 1999, 79 (12) : 1573 - 1582