Role of Glycated High Mobility Group Box-1 in Gastric Cancer

DOI Web Site PubMed 3 Citations 50 References Open Access
  • Shingo Kishi
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Yukiko Nishiguchi
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Kanya Honoki
    Department of Orthopedics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
  • Shiori Mori
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Rina Fujiwara-Tani
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Takamitsu Sasaki
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Kiyomu Fujii
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Isao Kawahara
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Kei Goto
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Chie Nakashima
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Akira Kido
    Department of Orthopedics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
  • Yasuhito Tanaka
    Department of Orthopedics, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
  • Yi Luo
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan
  • Hiroki Kuniyasu
    Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8521, Japan

Description

<jats:p>Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. Nε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.</jats:p>

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