NF-kappaB activation in esophageal adenocarcinoma: relationship to Barrett's metaplasia, survival, and response to neoadjuvant chemoradiotherapy.
OBJECTIVE
To examine the expression of the transcription factor nuclear factor kappa B (NF-kappaB) in Barrett's epithelium and adenocarcinoma and the impact of NF-kappaB expression on tumor stage and response to neoadjuvant chemotherapy and radiation therapy.


BACKGROUND
Progression of Barrett's esophagus to adenocarcinoma is associated with a wide range of cellular and molecular abnormalities. Nuclear factor-kappa B (NF-kappaB) regulates several genes involved in inflammatory, immune and apoptotic responses, but its role in esophageal inflammation and tumorigenesis has not been reported.


METHODS
Mobility shift assay was used to measure NF-kappaB activity in nuclear extracts of fresh-frozen biopsies from tumor and uninvolved tissues (n = 30) and esophageal cell lines OE33, SKGT-4, and OE21. RelA expression was assessed by immunohistochemical staining (n = 97). The NF-kappaB/RelA and IkappaB protein expressions were also examined by Western blotting.


RESULTS
NF-kappaB was not expressed in normal esophageal squamous epithelium, in contrast to increased expression in 40% of patients with Barrett's epithelium. Sixty-one percent of resected tumors (n = 97) displayed NF-kappaB immunoreactivity, and 87.5% of the NF-kappaB-positive tumors were Stage IIb and III compared with only 12.5% of patients with Stage I and IIa disease (P < 0.05). The expression of NF-kappaB inversely correlated with major or complete pathologic responses to neoadjuvant chemotherapy and radiation therapy, with 15/20 (75%) responders in the NF-kappaB-negative group compared with 7/38 (18%) in the NF-kappaB-positive group (P < 0.00001). Moreover, incubation of esophageal cell lines OE33, SKGT-4, and OE21 with deoxycholic acid or low pH induced NF-kappaB expression.


CONCLUSIONS
Bile acids and low pH induce NF-kappaB expression in esophageal cell lines. NF-kappaB activation is common in esophageal adenocarcinoma. In patients with Barrett's epithelium and an associated esophageal adenocarcinoma, there is a progressive expression of NF-kappaB through Barrett's tumorigenesis. The absence of NF-kappaB expression in esophageal adenocarcinoma correlates with response to neoadjuvant chemoradiotherapy and may be of value in predicting response to neoadjuvant therapy.
Abdel-Latif
Mohamed M M
MM
Department of Clinical Surgery, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin 8, Ireland.
O'Riordan
James
J
Windle
Henry J
HJ
Carton
Eleanor
E
Ravi
Nagunivan
N
Kelleher
Dermot
D
Reynolds
John V
JV
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001471:Barrett Esophagus / Q000235:genetics* / Q000473:pathology; D001647:Bile Acids and Salts / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017024:Chemotherapy, Adjuvant / Q000379:methods; D003840:Deoxycholic Acid / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016629:Esophagectomy / Q000379:methods; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D018714:Radiotherapy, Adjuvant / Q000379:methods; D016019:Survival Analysis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D016328:NF-kappa B; D003840:Deoxycholic Acid