Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.
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.
Clément
Geneviève
G
Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California San Francisco, 2340 Sutter St, San Francisco, CA 94115, USA.
Guilleret
Isabelle
I
He
Biao
B
Yagui-Beltrán
Adam
A
Lin
Yu-Ching
YC
You
Liang
L
Xu
Zhidong
Z
Shi
Yihui
Y
Okamoto
Junichi
J
Benhattar
Jean
J
Jablons
David
D
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*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D012097:Repressor Proteins; C485569:WIF1 protein, human; D002945:Cisplatin