title: Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.
abstract: The role of Wnt antagonists in the carcinogenesis of esophageal adenocarcinoma (EAC) remains unclear. We hypothesized that downregulation of the Wnt inhibitory factor-1 (WIF-1) might be involved in the neoplastic progression of Barrett's esophagus (BE). We analyzed the DNA methylation status of the WIF-1 promoter in normal, preneoplastic, and neoplastic samples from BE patients and in EAC cell lines. We investigated the role of WIF-1 on EAC cell growth and the chemosensitization of the cells to cisplatin. We found that silencing of WIF-1 correlated with promoter hypermethylation. EAC tissue samples showed higher levels of WIF-1 methylation compared to the matched normal epithelium. In addition, we found that WIF-1 hypermethylation was more frequent in BE samples from patients with EAC than in BE samples from patients who had not progressed to EAC. Restoration of WIF-1 in cell lines where WIF-1 was methylation-silenced resulted in growth suppression. Restoration of WIF-1 could sensitize the EAC cells to the chemotherapy drug cisplatin. Our results suggest that silencing of WIF-1 through promoter hypermethylation is an early and common event in the carcinogenesis of BE. Restoring functional WIF-1 might be used as a new targeted therapy for the treatment of this malignancy.
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California San Francisco, 2340 Sutter St, San Francisco, CA 94115, USA.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Clément
authors.forename: Isabelle
authors.initials: I
authors.lastname: Guilleret
authors.forename: Biao
authors.initials: B
authors.lastname: He
authors.forename: Adam
authors.initials: A
authors.lastname: Yagui-Beltrán
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lin
authors.forename: Liang
authors.initials: L
authors.lastname: You
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.forename: Yihui
authors.initials: Y
authors.lastname: Shi
authors.forename: Junichi
authors.initials: J
authors.lastname: Okamoto
authors.forename: Jean
authors.initials: J
authors.lastname: Benhattar
authors.forename: David
authors.initials: D
authors.lastname: Jablons
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001471:Barrett Esophagus / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D012097:Repressor Proteins; C485569:WIF1 protein, human; D002945:Cisplatin