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Cell and Tumor Biology |
1 Institute of Molecular and Cell Biology, Proteos; 2 Oncology Research Institute; and Departments of 3 Pathology and 4 Medicine, Faculty of Medicine, National University of Singapore, Singapore
Requests for reprints: Yoshiaki Ito, Institute of Molecular and Cell Biology, Proteos, 61 Biopolis Drive, Singapore 138673. Phone: 65-6586-9646; Fax: 65-6779-1117; E-mail: itoy{at}imcb.a-star.edu.sg.
Loss of RUNX3 expression is suggested to be causally related to gastric cancer as 45% to 60% of gastric cancers do not express RUNX3 mainly due to hypermethylation of the RUNX3 promoter. Here, we examined for other defects in the properties of RUNX3 in gastric cancers that express RUNX3. Ninety-seven gastric cancer tumor specimens and 21 gastric cancer cell lines were examined by immunohistochemistry using novel anti-RUNX3 monoclonal antibodies. In normal gastric mucosa, RUNX3 was expressed most strongly in the nuclei of chief cells as well as in surface epithelial cells. In chief cells, a significant portion of the protein was also found in the cytoplasm. RUNX3 was not detectable in 43 of 97 (44%) cases of gastric cancers tested and a further 38% showed exclusive cytoplasmic localization, whereas only 18% showed nuclear localization. Evidence is presented suggesting that transforming growth factor-ß is an inducer of nuclear translocation of RUNX3, and RUNX3 in the cytoplasm of cancer cells is inactive as a tumor suppressor. RUNX3 was found to be inactive in 82% of gastric cancers through either gene silencing or protein mislocalization to the cytoplasm. In addition to the deregulation of mechanisms controlling gene expression, there would also seem to be at least one other mechanism controlling nuclear translocation of RUNX3 that is impaired frequently in gastric cancer.
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  M. Zhang, R. Xie, W. Hou, B. Wang, R. Shen, X. Wang, Q. Wang, T. Zhu, J. H. Jonason, and D. Chen PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation J. Cell Sci., May 1, 2009; 122(9): 1382 - 1389. [Abstract] [Full Text] [PDF]
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 S. Fujii, K. Ito, Y. Ito, and A. Ochiai Enhancer of Zeste Homologue 2 (EZH2) Down-regulates RUNX3 by Increasing Histone H3 Methylation J. Biol. Chem., June 20, 2008; 283(25): 17324 - 17332. [Abstract] [Full Text] [PDF]
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 Z. Peng, D. Wei, L. Wang, H. Tang, J. Zhang, X. Le, Z. Jia, Q. Li, and K. Xie RUNX3 Inhibits the Expression of Vascular Endothelial Growth Factor and Reduces the Angiogenesis, Growth, and Metastasis of Human Gastric Cancer. Clin. Cancer Res., November 1, 2006; 12(21): 6386 - 6394. [Abstract] [Full Text] [PDF]
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 Q. C. Lau, E. Raja, M. Salto-Tellez, Q. Liu, K. Ito, M. Inoue, T. C. Putti, M. Loh, T. K. Ko, C. Huang, et al. RUNX3 Is Frequently Inactivated by Dual Mechanisms of Protein Mislocalization and Promoter Hypermethylation in Breast Cancer. Cancer Res., July 1, 2006; 66(13): 6512 - 6520. [Abstract] [Full Text] [PDF]
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 T. Yano, K. Ito, H. Fukamachi, X.-Z. Chi, H.-J. Wee, K.-i. Inoue, H. Ida, P. Bouillet, A. Strasser, S.-C. Bae, et al. The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factor {beta}-Induced Apoptosis Mol. Cell. Biol., June 15, 2006; 26(12): 4474 - 4488. [Abstract] [Full Text] [PDF]
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Cytoplasmic Retention of RUNX3 Cancer Res., March 15, 2006; 66(6): 3345 - 3345. [Full Text] [PDF]
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