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Pituitary Tumor-Transforming 1 Increases Cell Motility and Promotes Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma

¹ Division of Gastroenterology, Department of Medicine, and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Department of Surgery, Graduate School of Medicine, and ³ Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; and ⁴ Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences Research, University of Toyama, Toyama, Japan

Requests for reprints: Fumiaki Sato, Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Main Building A320, Shimoadachi-cho 46-29, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-9559; Fax: 81-75-753-9557; E-mail: fsato{at}pharm.kyoto-u.ac.jp, or Stephen J. Meltzer, Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Room 112, 1503 East Jefferson Street, Baltimore, MD 21231. Phone: 410-502-6071; Fax: 410-502-1099; E-mail: smeltzer{at}jhmi.edu.

Key Words: Esophageal squamous cell carcinoma • PTTG1 • Lymph node metastasis • cell motility • siRNA

Human pituitary tumor-transforming 1 (PTTG1)/securin is a putative oncoprotein that is overexpressed in various tumor types. However, the involvement of PTTG1 in gastrointestinal cancer development and progression remains unclear. In this study, we investigated the clinical significance and biological effects of PTTG1 in esophageal squamous cell carcinoma (ESCC). Immunohistochemical studies performed on 113 primary ESCC specimens revealed a high prevalence of PTTG1 overexpression (60.2%), which was significantly associated with lymph node metastasis (regional, P = 0.042; distant, P = 0.005), advanced tumor stage (P = 0.028), and poorer overall survival (P = 0.017, log-rank test; P = 0.044, Cox proportional hazard model). Eleven ESCC cell lines expressed PTTG1 protein at levels 2.4 to 6.6 times higher than those in normal esophageal epithelial cells (HEEpiC). PTTG1 protein expression was confined to the nucleus in HEEpiC cells but present in both the cytoplasm and nucleus in ESCC cells. Two small interfering RNAs (siRNA) inhibited PTTG1 mRNA and protein expression in three ESCC cell lines by 77% to 97%. In addition, PTTG1 down-regulation by these siRNAs significantly reduced cell motility in all three ESCC cell lines (P < 0.01) in vitro, as well as popliteal lymph node metastases of ESCC cells in nude mice (P = 0.020). Global gene expression profiling suggested that several members of the Ras and Rho gene families, including RRAS, RHOG, ARHGAP1, and ARHGADIA, represented potential downstream genes in the PTTG1 pathway. Taken together, these findings suggest that PTTG1 overexpression promotes cell motility and lymph node metastasis in ESCC patients, leading to poorer survival. Thus, PTTG1 constitutes a potential biomarker and therapeutic target in ESCCs with lymph node metastases. [Cancer Res 2008;68(9):3214–24]