title: SMYD2 overexpression is associated with tumor cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas.
abstract: Human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease, and there are no suitable prognostic or predictive markers. The SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase for histone H3K36 and p53K370, that regulates transcription was previously found to be a cancer-promoting gene in esophageal squamous cell carcinoma. In this study, we investigated whether SMYD2 is a possible oncogene and a prognostic indicator in HPV-unrelated, multiple and nonmultiple HNSCC. Among 197 HPV-unrelated HNSCC cases, overexpression of SMYD2 protein was detected in 75 (60%) of 126 nonmultiple cases and 51 (70%) of 71 multiple cases. In nonmultiple cases, patients with SMYD2-overexpressing tumors had a worse overall survival rate than did those with nonexpressing tumors (P = .017, log-rank test), and SMYD2 positivity was independently associated with overall survival in the multivariate analysis (P = .003). In both nonmultiple and multiple groups, the combination of SMYD2 and p53 immunopositivity was a significant prognostic indicator (P = .027 and .015). In 5 HNSCC cell lines, overexpression of SMYD2 messenger RNA and protein was observed, but there was no notable amplification at 1q32-41.1. The proliferation of UM-SCC-17B HPV-unrelated HNSCC cell line was inhibited by knockdown of SMYD2 gene expression. These findings suggest that SMYD2 plays a role in tumor progression and might be a useful prognosticator in HPV-unrelated, nonmultiple HNSCC.
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan; Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan; Department of Clinical Laboratory, JR Tokyo General Hospital, Tokyo 151-8528, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ohtomo-Oda
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Komatsu
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Mori
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sekine
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Hirajima
authors.affiliation: Department of Head and Neck Oncology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Yoshimoto
authors.affiliation: Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
authors.forename: Yae
authors.initials: Y
authors.lastname: Kanai
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan; Department of Basic Pathology, National Defense Medical College, Saitama 359-8513, Japan. Electronic address: htsuda@ndmc.ac.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tsuda
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C512569:SMYD2 protein, human
keywords: HPV unrelated; Head and neck squamous cell carcinoma; Multiple cancer; SMYD2; Second primary cancer; p53