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Restoration of RUNX3 enhances transforming growth factor-β-dependent p21 expression in a biliary tract cancer cell line

  1. Kazunori Hasegawa1,
  2. Shujiro Yazumi1,
  3. Manabu Wada1,
  4. Toshiharu Sakurai1,
  5. Masaya Kida1,
  6. Junichi Yamauchi1,
  7. Hiroshi Hisatsune1,
  8. Shinsuke Tada1,
  9. Hiroshi Ida1,
  10. Yuenn Nakase2,
  11. Chohei Sakakura2,
  12. Akeo Hagiwara2,
  13. Tsutomu Chiba1,*

Article first published online: 25 APR 2007

DOI: 10.1111/j.1349-7006.2007.00460.x

Issue

Cancer Science

Cancer Science

Volume 98, Issue 6, pages 838–843, June 2007

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How to Cite

Hasegawa, K., Yazumi, S., Wada, M., Sakurai, T., Kida, M., Yamauchi, J., Hisatsune, H., Tada, S., Ida, H., Nakase, Y., Sakakura, C., Hagiwara, A. and Chiba, T. (2007), Restoration of RUNX3 enhances transforming growth factor-β-dependent p21 expression in a biliary tract cancer cell line. Cancer Science, 98: 838–843. doi: 10.1111/j.1349-7006.2007.00460.x

Author Information

  1. 1

    Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507;

  2. 2

    Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan

* To whom correspondence should be addressed. E-mail: chiba@kuhp.kyoto-u.ac.jp.

Publication History

  1. Issue published online: 25 APR 2007
  2. Article first published online: 25 APR 2007
  3. (Received September 24, 2006/Revised January 13, 2007/Accepted February 2, 2007/Online publication March 30, 2007)

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RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region commonly inactivated by deletion and methylation in various human tumors. To elucidate the role of RUNX3 in transforming growth factor (TGF)-β signaling in biliary tract cancer, we transfected Mz-ChA-2 cells, which do not express RUNX3 but have intact TGF-β type II receptor and SMAD4 genes, with the RUNX3 expression plasmid pcDNA3.1/RUNX3 or with the vector pcDNA3.1 as a control. Four Mz-ChA-2/RUNX3 clones and one control clone were obtained. Although TGF-β1 only slightly inhibited growth of the control cells, growth inhibition and TGF-β-dependent G1 arrest were significantly enhanced in the RUNX3-transfected clones. None of the clones, however, exhibited apoptosis. The slightly increased TGF-β1-induced p21 expression in the control clone was strongly enhanced in the RUNX3-transfected clones, and was accompanied by augmented decreases in the expression of cyclins D1 and E. When RUNX3 small interfering RNA was added, TGF-β-dependent induction of p21 was reduced in the RUNX3-transfected clones. Xenografts of the clones in nude mice demonstrated that tumorigenicity was significantly decreased in the RUNX3-transfected clones in inverse proportion to the expression levels of RUNX3. Based on these results, RUNX3 is involved in TGF-β-induced expression of p21 and the resulting induction of TGF-β-dependent G1 arrest. (Cancer Sci 2007; 98: 838–843)

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