Carcinogenesis Advance Access published online on May 7, 2009
Carcinogenesis, doi:10.1093/carcin/bgp116
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Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous-cell carcinoma
1 Department of Molecular Cytogenetics and School of Biomedical Science, Medical Research Institute and School of Biomedical Science
2 Department of Genome Medicine, Hard Tissue Genome Research Center
3 Global Center of Excellence (GCOE) Program; International Research Center for Molecular Science in Tooth and Bone Diseases, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo-ku, Tokyo 113-8510, Japan
4 Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kawaramachi Hirokoji Kamigyo-ku, Kyoto 602-8566, Japan
5 Department of Basic Pathology
6 Department of Surgery, National Defense Medical College, 3-2 Namiki-chou Tokorozawa, Saitama 359-8513, Japan
7 Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
All correspondence: Johji Inazawa, M.D., Ph.D., Department of Molecular Cytogenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan, Tel: 03-5803-5820, Fax: 03-5803-0244, E-mail: johinaz.cgen{at}mri.tmd.ac.jp
Although we have identified two putative targets, ATF3 and CENPF, for a frequently gained/amplified region around 1q32-q41 in esophageal squamous-cell carcinoma (ESCC), it is possible that other amplification targets remain to be identified. In this study, we tested whether SET and MYND domain-containing protein-2 (SMYD2), located between those two genes and encoding a lysine methyltransferase for histone H3K36 and p53K370 that regulates transcription and inhibits transactivation activity, respectively, acts as a cancer-promoting gene through activation/overexpression in ESCC. Frequent overexpression of SMYD2 mRNA and protein was observed in KYSE150 cells with remarkable amplification at 1q32-41.1 and other ESCC cell lines (21/43 lines, 48.8%). Overexpression of SMYD2 protein was frequently detected in primary tumor samples of ESCC (117/153 cases, 76.5%) as well, and significantly correlated with gender, venous invasion, the pT category in the TNM classification, and status of recurrence. Patients with SMYD2-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and SMYD2 positivity was independently associated with a worse outcome in the multivariate analysis. Knockdown of SMYD2 expression inhibited and ectopic overexpression of SMYD2 promoted the proliferation of ESCC cells in a TP53 mutation-independent but SMYD2 expression-dependent manner. These findings suggest that SMYD2 plays an important role in tumor cell proliferation through its activation/overexpression, and highlight its usefulness as a prognosticator and potential therapeutic target in ESCC.
Key Words: esophageal squamous-cell carcinoma • SMYD2 • overexpression • prognosticator • proliferation
Received February 15, 2009; revised April 23, 2009; accepted May 2, 2009.