title: Pituitary tumor-transforming 1 increases cell motility and promotes lymph node metastasis in esophageal squamous cell carcinoma.
abstract: 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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimada
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Kan
authors.forename: Stefan
authors.initials: S
authors.lastname: David
authors.forename: Yulan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Mori
authors.forename: Rachana
authors.initials: R
authors.lastname: Agarwal
authors.forename: Bogdan
authors.initials: B
authors.lastname: Paun
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jin
authors.forename: Alexandru
authors.initials: A
authors.lastname: Olaru
authors.forename: James P
authors.initials: JP
authors.lastname: Hamilton
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: John M
authors.initials: JM
authors.lastname: Abraham
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement; D002478:Cells, Cultured; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D064249:Securin; D016019:Survival Analysis; D014162:Transfection
chemical_list: D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D064249:Securin; C578002:pituitary tumor-transforming protein 1, human