title: Epithelial cell-derived periostin functions as a tumor suppressor in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14ARF/Mdm2 signaling pathway.
abstract: Periostin is usually considered as an oncogene in diverse human cancers, including breast, prostate, colon, esophagus, and pancreas cancers, whereas it acts as a tumor suppressor in bladder cancer. In gastric cancer, it has been demonstrated that periglandular periostin expression is decreased whereas stromal periostin expression is significantly increased as compared with normal gastric tissues. Moreover, periostin produced by stromal myofibroblasts markedly promotes gastric cancer cell growth. These observations suggest that periostin derived from different types of cells may play distinct biological roles in gastric tumorigenesis. The aim of this study was to explore the biological functions and related molecular mechanisms of epithelial cell-derived periostin in gastric cancer. Our data showed that periglandular periostin was significantly down-regulated in gastric cancer tissues as compared with matched normal gastric mucosa. In addition, its expression in metastatic lymph nodes was significantly lower than that in their primary cancer tissues. Our data also demonstrated that periglandular periostin expression was negatively associated with tumor stage. More importantly, restoration of periostin expression in gastric cancer cells dramatically suppressed cell growth and invasiveness. Elucidation of the mechanisms involved revealed that periostin restoration enhanced Rb phosphorylation and sequentially activated the transcription of E2F1 target gene p14(ARF), leading to Mdm2 inactivation and the stabilization of p53 and E-cadherin proteins. Strikingly, these effects of periostin were abolished upon Rb deletion. Collectively, we have for the first time demonstrated that epithelial cell-derived periostin exerts tumor-suppressor activities in gastric cancer through stabilizing p53 and E-cadherin proteins via the Rb/E2F1/p14(ARF)/Mdm2 signaling pathway.
authors.affiliation: a Department of Endocrinology ; The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine ; Xi'an , The People's Republic of China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lv
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Jiao
authors.initials: J
authors.lastname: Fu
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Pu
authors.initials: P
authors.lastname: Chen
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D015703:Antigens, CD; D017209:Apoptosis; D015820:Cadherins / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C512835:POSTN protein, human; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: 3-[4; 5-dimethylthiazol-2-yl]-2; 5-diphenyl tetrazolium bromide; NSCLC; Abbreviations: Akt/PKB; Dulbecco's modified Eagles medium; DMSO; E-cadherin; E2F transcription factor 1; ECM; Ethylenediaminetetraacetic acid; EGFR; Gastric cancer; Mdm2; Rb/E2F1 pathway; Reverse-transcription polymerase chain reaction; SDS-PAGE; Roswell Park Memorial Institute 1640; RT-PCR; Sentrin-specific protease 8; shRNA; dimethyl sulfoxide; E2F1; enzyme linked immunosorbent assay; EMT; epidermal growth factor receptor; ELISA; epithelial-to-mesenchymal transition; ESCC; esophageal squamous cell carcinoma; FAK; extracellular matrix; EDTA; fluoresceine isothiocyanate; HRP; focal adhesion kinase; FITC; horseradish peroxidase; HC; immunohistochemistry; Mdm2; metalloproteinases; MTT; mouse double minute 2; MMPs; non-small-cell lung cancer; PBS; p53; periostin; phosphate buffered saline; PI3K; phosphatidylinositol 3-kinase; PVDF; polyvinylidene fluoride; Rb; retinoblastoma; RPMI 1640; serine/threonine kinase/protein kinase B; DMEM; short hairpin RNA.; sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SENP8