title: AEG-1 is a target of perifosine and is over-expressed in gastric dysplasia and cancers.
abstract: BACKGROUND
  Perifosine, an alkylphospholipid, is an Akt inhibitor which inhibits the growth of diverse cancer cells. We have reported its inhibitory effects on the growth of gastric cancer cells recently, but its molecular mechanisms are still largely unknown.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the effect and regulatory mechanism of perifosine in gastric cancer.
  
  
  METHODS
  Cell viability was determined by sulforhodamine B assay after transiently transfected with AEG-1 specific siRNAs. qRT-PCR and western blot assay were used to determine the mRNA expression and proteins levels of cell signaling molecules examined. Immunohistochemistry was used to detect the AEG-1 expression in 87 gastric carcinomas, 60 dysplasia, and 47 normal gastric mucosa.
  
  
  RESULTS
  Perifosine decreased AEG-1 gene expression along with inhibition of Akt/GSK3β/C-MYC signaling pathway. Knockdown of AEG-1 using siRNA led to significant down-regulation of cyclin D1 expression at both mRNA level and protein level, and inhibited the growth of gastric cancer cells. AEG-1 expression was elevated in gastric dysplasia and cancer tissues compared to normal gastric mucosa (P < 0.01). AEG-1 over-expression correlated with diffuse type of gastric cancer and advanced tumor stages.
  
  
  CONCLUSIONS
  Perifosine inhibits the growth of gastric cancer cells possibly through inhibition of the Akt/GSK3β/C-MYC signaling pathway-mediated down-regulation of AEG-1 that subsequently down-regulated cyclin D1. AEG-1 may play an important role in the carcinogenesis and progression of gastric cancer and could be a therapeutic target of perifosine.
authors.affiliation: Department of Pathology, Nanjing Medical University Affiliated Nanjing Hospital (Nanjing First Hospital), Nanjing, 210006, Jiangsu, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Liang
authors.forename: Dongxiao
authors.initials: D
authors.lastname: Liu
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Ma
authors.forename: Sulan
authors.initials: S
authors.lastname: Zhai
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D015815:Cell Adhesion Molecules / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects; D013272:Stomach Diseases / Q000378:metabolism* / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; C489427:MYC protein, human; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins; D010767:Phosphorylcholine; D019938:Cyclin D1; C105905:perifosine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
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