title: Clinicopathologic significance and function of mammalian target of rapamycin activation in esophageal squamous cell carcinoma.
abstract: Mammalian target of rapamycin (mTOR) has emerged as a key regulator of cell metabolism, growth, and proliferation. Despite the increasing significance of mTOR signaling in cancer cell cycle and proliferation, the clinical significance of activated mTOR in esophageal squamous cell carcinoma and its role in esophageal cancer cell proliferation and invasion remain unclear. Here, we show that both high levels of phosphorylated-mTOR and an increased ratio of phosphorylated-mTOR/mTOR (ratio ≥0.2) were significantly associated with shortened disease-specific survival in 165 patients with esophageal squamous cell carcinoma in univariate analysis (P = .047 for phosphorylated-mTOR, P = .021 for phosphorylated-mTOR/mTOR); phosphorylated-mTOR and phosphorylated-mTOR/mTOR remained independent prognostic factors after adjusting for age, TNM stage, chemotherapy, and radiation therapy in multivariate analysis (hazard ratio, 1.67, P = .025 for phosphorylated-mTOR; hazard ratio, 1.95, P = .006 for phosphorylated-mTOR/mTOR). Moreover, down-regulation of mTOR or mTOR complex components led to attenuation of proliferation, migration, and invasion of esophageal squamous cell carcinoma cell lines through suppression of cyclin D1 expression. Collectively, our findings suggest that phosphorylated-mTOR and the ratio of phosphorylated-mTOR/mTOR are closely linked to tumor progression and represent independent prognostic factors in esophageal squamous cell carcinoma, thereby providing a potential therapeutic target for this malignancy.
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.forename: Gia Cac
authors.initials: GC
authors.lastname: Chau
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Jang
authors.forename: Seung Im
authors.initials: SI
authors.lastname: Lee
authors.forename: Suhkneung
authors.initials: S
authors.lastname: Pyo
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Um
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D019938:Cyclin D1 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019938:Cyclin D1; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases