Runt-related transcription factor 3 reverses epithelial–mesenchymal transition in hepatocellular carcinoma

Authors

  • Shigetomi Tanaka,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
    • S.T. and H.S. contributed equally to this work

  • Hidenori Shiraha,

    Corresponding author
    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    • Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
    Search for more papers by this author
    • S.T. and H.S. contributed equally to this work

    • Tel.: [+81-86-235-7219], Fax: +[81-86-225-5991]

  • Yutaka Nakanishi,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Shin-Ichi Nishina,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Minoru Matsubara,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Shigeru Horiguchi,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Nobuyuki Takaoka,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Masaya Iwamuro,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Junro Kataoka,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Kenji Kuwaki,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Hiroaki Hagihara,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Junichi Toshimori,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Hideki Ohnishi,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Akinobu Takaki,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Shinichiro Nakamura,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Kazuhiro Nouso,

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Takahito Yagi,

    1. Department of Gastroenterological Surgery, Transplant, and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author
  • Kazuhide Yamamoto

    1. Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    Search for more papers by this author

Abstract

Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelial–mesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC.

Ancillary