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Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma
George S Watts1, Nhan L Tran, Michael E Berens
1Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. gwatts@azcc.arizona.edu
Abstract:
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.
Insights
New research identifies Fn14 as a potential therapeutic target for esophageal adenocarcinoma (EAC). This protein, overexpressed in EAC, influences tumor invasion and disease progression, offering a novel avenue for treatment development.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Esophageal adenocarcinoma (EAC) has a poor prognosis, necessitating novel therapeutic targets.
- Current therapies for EAC exhibit limited efficacy and survival rates.
- Identifying new molecular targets is crucial for advancing EAC treatment strategies.
Purpose of the Study:
- To identify and validate novel therapeutic targets for esophageal adenocarcinoma (EAC).
- To investigate the role of TNFRSF12A/Fn14 in EAC progression and therapeutic response.
- To explore Fn14 as a potential biomarker and therapeutic target in EAC.
Main Methods:
- Microarray analysis (Affymetrix U133A GeneChips) was employed for expression profiling.
- Gene expression data from normal esophagus, Barrett's esophagus, EAC tissues, and EAC cell lines were analyzed.
- Validation involved cell line studies (transwell assays) and immunohistochemistry on patient tissue microarrays.
Main Results:
- Overexpression of 200 transcripts in EAC compared to normal and Barrett's esophagus tissues was identified.
- TNFRSF12A/Fn14 was selected as a potential target due to its overexpression in EAC.
- Fn14 modulated tumor cell invasion in EAC, and its expression correlated with disease progression.
Conclusions:
- Fn14 plays a novel role in EAC cell invasion, distinct from its previously known role in cell survival.
- Fn14 protein expression increases with EAC disease progression, suggesting its potential as a biomarker.
- Fn14 represents a promising therapeutic target for esophageal adenocarcinoma, warranting further investigation.
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