title: Phosphorylated mTOR expression correlates with podoplanin expression and high tumor grade in esophageal squamous cell carcinoma.
abstract: Mechanistic (or mammalian) target of rapamycin (mTOR) plays important roles in cell growth and proliferation. In esophageal squamous cell carcinoma (SCC), high expression of phosphorylated (activated) mTOR (p-mTOR) has been reported as an adverse prognostic factor in some but not all studies. The signals of mTOR pathway and mitogen-activated protein kinase (MAPK) pathway converge on 4E-binding protein 1 (4EBP1), which drives the downstream proliferative signals. We previously found that high expression of phosphorylated 4EBP1 (p-4EBP1) is an adverse prognostic factor in esophageal SCC. Podoplanin is a type-1 transmembrane glycoprotein expressed in various normal human tissues, including lymphatic endothelium. Our previous study showed that high podoplanin expression correlates with clinical nodal metastasis, which is associated with short survival in esophageal SCC. In current study, we investigated p-mTOR expression by immunohistochemistry in 75 cases of surgically resected esophageal SCC. The result was correlated with p-4EBP1 expression, podoplanin expression, clinicopathologic features and patient survival. We found that high p-mTOR expression was significantly associated with high podoplanin expression (P = 0.0030) and high tumor grade (P = 0.0014). No correlation with p-4EBP1 expression, patient survival or other clinicopathologic features was found. Recently, podoplanin expression in astrocytic brain tumors was found to be regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT/activator protein-1 (AP-1) pathway. Similarly, mTOR is activated by a PI3K/AKT/mTOR pathway. The association of p-mTOR and podoplanin expression in our study could be due to a common upstream pathway. Since both mTOR and podoplanin are potential therapeutic targets, the possible benefit of combined targeted therapy warrants further investigation.
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Chuang
authors.affiliation: Chang Gung Molecular Medicine Research Center and Graduate Institute of Basic Medical Sciences, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Yu-Sun
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Yin-Kai
authors.initials: YK
authors.lastname: Chao
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Chi-Ju
authors.initials: CJ
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Shir-Hwa
authors.initials: SH
authors.lastname: Ueng
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Chiu-Yueh
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Yun-Hen
authors.initials: YH
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Chen-Kan
authors.initials: CK
authors.lastname: Tseng
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Hsien-Kun
authors.initials: HK
authors.lastname: Chang
authors.affiliation: Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Yung-Liang
authors.initials: YL
authors.lastname: Wan
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan ; Chang Gung Molecular Medicine Research Center and Graduate Institute of Basic Medical Sciences, Chang Gung Memorial Hospital and Chang Gung University College of Medicine Taoyuan, Taiwan.
authors.forename: Chuen
authors.initials: C
authors.lastname: Hsueh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D058570:TOR Serine-Threonine Kinases; C117468:PDPN protein, human; D000098853:Podoplanin
keywords: 4E-binding protein 1 (4EBP1); Mechanistic target of rapamycin (mTOR); esophagus; podoplanin; squamous cell carcinoma; tumor grade