title: Expression of key mTOR pathway components in pancreatic ductal adenocarcinoma: A multicenter study for clinicopathologic and prognostic significance.
abstract: Thus far, clinicopathologic and prognostic significance of mTOR signaling pathway in pancreatic ductal adenocarcinoma (PDAC) remains unclear, although it is involved in PDAC. In this study, total (t-) and phosphorylated (p-) mTOR, 4EBP1 and P70S6K, were investigated. It was found that most aforementioned proteins were related to malignant and progressive phenotypes, especially histological grade, in independent development and validation cohorts of PDAC. In the development cohort, high expression and/or phosphorylation of mTOR, 4EBP1 and P70S6K were all univariately associated with poor tumor-specific survival, whereas p-mTOR, p-4EBP1 and p-P70S6K, adjusted for clinicopathologic variables, unlike t-mTOR, t-4EBP1 and t-P70S6K, were shown to be independent prognostic factors in multivariate analysis. Interestingly and importantly, the independently significant impacts of p-mTOR and p-4EBP1 on tumor-specific survival were confirmed in the validation cohort. Contrarily, t-mTOR and t-4EBP1 were only univariately significant, while t-P70S6K and p-P70S6K were not prognostic. Finally, mTOR and EIF4EBP1, genes encoding mTOR and 4EBP1, also serve as prognostic indicators in the publicly available TCGA RNA-sequencing database. Our data indicate that expression and activation, especially the latter, of mTOR and 4EBP1, might have clinicopathologic and prognostic significance in PDAC.
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Da
authors.initials: D
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Liang
authors.affiliation: Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Wei-Xun
authors.initials: WX
authors.lastname: Zhou
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
authors.forename: Jian-Yu
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Shanghai Medical College of Fudan University, Shanghai 200032, China.
authors.forename: Shu-Heng
authors.initials: SH
authors.lastname: Jiang
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Tai-Ping
authors.initials: TP
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China.
authors.forename: Lei
authors.initials: L
authors.lastname: You
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China. Electronic address: gjcpumch@163.com.
authors.forename: Jun-Chao
authors.initials: JC
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100730, China. Electronic address: zhao8028@263.net.
authors.forename: Yu-Pei
authors.initials: YP
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000401:mortality / Q000473:pathology*; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology*; D010750:Phosphoproteins / Q000502:physiology; D011379:Prognosis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: 4EBP1; Immunohistochemistry; P70S6K; Pancreatic ductal adenocarcinoma; Prognostic factor; mTOR