title: Identification of the putative intestinal stem cell marker doublecortin and CaM kinase-like-1 in Barrett's esophagus and esophageal adenocarcinoma.
abstract: OBJECTIVE
  In Barrett's esophagus (BE), the normal esophageal squamous epithelium is replaced with a specialized metaplastic columnar epithelium. BE is a premalignant lesion that can progress to esophageal adenocarcinoma (EAC). Currently, there are no early molecular indicators that would predict progression from BE to EAC. As the only permanent residents of the epithelium, stem cells have been implicated in this metaplastic progression. The aim of the present study was to determine the expression of doublecortin and CaM kinase-like-1 (DCAMKL-1) and other putative gastrointestinal stem cell markers in normal esophageal mucosa (NEM), BE, and EAC.
  
  
  METHODS
  Human NEM, BE, EAC, and multitissue microarrays were analyzed for DCAMKL-1, and immunohistochemically scored based on staining intensity and tissue involvement, with epithelia and stroma scored separately. Total RNA isolated from BE and paired NEM was subjected to real-time reverse-transcription-polymerase chain reaction analysis for DCAMKL-1, leucine-rich repeat-containing G-protein-coupled receptor (LGR5), and Musashi-1 (Msi-1) mRNA expression.
  
  
  RESULTS
  DCAMKL-1 was minimally expressed in squamous NEM, but increased in BE (with and without dysplasia) and EAC tissues. In EAC, we found increased stromal DCAMKL-1 staining compared to adjacent epithelia. Within the submucosa of dysplastic BE tissues, an increase in the endothelial cell expression of DCAMKL-1 was observed. Finally, an upregulation of DCAMKL-1, LGR5, and Msi-1 mRNA was seen in BE compared to squamous NEM.
  
  
  CONCLUSIONS
  In the present study, we report the progressive increase of DCAMKL-1 expression in BE from dysplasia to EAC. Furthermore, there was an increase in putative stem cell markers DCAMKL-1, LGR5, and Msi-1 mRNA. Taken together, these data suggest that the regulation of resident stem cells might play an important role in the progression of BE to EAC.
authors.affiliation: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Vega
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.forename: Stan A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Qu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Reed
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weygant
authors.forename: Rama
authors.initials: R
authors.lastname: Ramanujam
authors.forename: Rhonda
authors.initials: R
authors.lastname: Souza
authors.forename: Mohammad
authors.initials: M
authors.lastname: Madhoun
authors.forename: Joshua
authors.initials: J
authors.lastname: Whorton
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D001471:Barrett Esophagus / Q000378:metabolism* / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000089742:Doublecortin-Like Kinases; D004938:Esophageal Neoplasms / Q000378:metabolism*; D004947:Esophagus / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; C116884:LGR5 protein, human; C491297:MSI1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D043562:Receptors, G-Protein-Coupled; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases