Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma.
Given the poor survival rate and efficacy of current therapy for esophageal adenocarcinoma (EAC), there is a need to identify and develop new therapeutic targets for treatment. Microarray analysis (Affymetrix U133A GeneChips, Robust Multi-Chip Analysis) was used to expression profile 11 normal squamous and 18 Barrett's esophagus biopsies, 7 surgically resected EACs and 3 EAC cell lines. Two hundred transcripts representing potential therapeutic targets were identified using the following criteria: significant overexpression in EAC by analysis of variance (p = 0.05, Benjamini Hochberg false discovery rate); 3-fold increase in EAC relative to normal and Barrett's esophagus and expression in at least 2 of the 3 EAC cell lines. From the list of potential targets we selected TNFRSF12A/Fn14/TWEAK receptor, a tumor necrosis factor super-family receptor, for further validation based on its reported role in tumor cell survival and potential as a target for therapy. Fn14 protein expression was confirmed in SEG-1 and BIC-1 cell lines, but Fn14 was not found to affect tumor cell survival after exposure to chemotherapeutics as expected. Instead, a novel role in EAC was discovered in transwell assays, in which modulating Fn14 expression affected tumor cell invasion. Fn14's potential as a therapeutic target was further supported by immunohistochemistry on a tissue microarray of patient samples that showed that Fn14 protein expression increased with disease progression in EAC.
Watts
George S
GS
Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. gwatts@azcc.arizona.edu
Tran
Nhan L
NL
Berens
Michael E
ME
Bhattacharyya
Achyut K
AK
Nelson
Mark A
MA
Montgomery
Elizabeth A
EA
Sampliner
Richard E
RE
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001706:Biopsy; D002460:Cell Line; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D000074050:TWEAK Receptor
D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor