title: Aberrantly methylated PKP1 in the progression of Barrett's esophagus to esophageal adenocarcinoma.
abstract: The aberrant DNA methylation of tumor suppressor genes occurs frequently in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) and likely affects the initiation and progression of BE to EAC. In the present study, we discovered PKP1 as a novel methylated gene in EAC and then investigated the role of loss of PKP1, a constituent of the desmosome complex found in stratified epithelial layers, on the behavior of Barrett's esophagus and esophageal adenocarcinoma cells. By using primary esophageal tissue samples we determined that PKP1 was rarely methylated in normal squamous esophagus (5/55; 9.1%) and BE (5/39; 12.8%) and more frequently methylated in Barrett's esophagus with high-grade dysplasia (HGD) or EAC (20/60; 33.3%; P < 0.05). Furthermore, PKP1 levels were decreased in BE and HGD/EAC cases compared to normal squamous esophagus cases. Knockdown of PKP1 in the BE cell lines CP-A and CP-D (both normally express PKP1) resulted in increased cell motility. Thus, PKP1 loss secondary to promoter methylation, as well as other mechanisms, may promote the progression of BE to EAC in a subset of patients via decreased desmosome assembly and increased cell motility.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. akaz@fhcrc.org
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kaz
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Luo
authors.forename: Slavomir
authors.initials: S
authors.lastname: Dzieciatkowski
authors.forename: Amitabh
authors.initials: A
authors.lastname: Chak
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Upton
authors.forename: Rom S
authors.initials: RS
authors.lastname: Leidner
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001471:Barrett Esophagus / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D002465:Cell Movement; D019175:DNA Methylation; D003896:Desmosomes / Q000378:metabolism; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C495335:PKP1 protein, human; D051191:Plakophilins; D012333:RNA, Messenger; D034741:RNA, Small Interfering