NF-κB Activation in Esophageal Adenocarcinoma

Abstract

Objective:To examine the expression of the transcription factor nuclear factor kappa B (NF-B) in Barrett's epithelium and adenocarcinoma and the impact of NF-B expression on tumor stage and response to neoadjuvant chemotherapy and radiation therapy. Summary Background Data: Progression of Barrett's esophagus to adenocarcinoma is associated with a wide range of cellular and molecular abnormalities. Nuclear factor-kappa B (NF-B) 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-B activity in nuclear extracts of fresh-frozen biopsies from tumor and uninvolved tissues (n ϭ 30) and esophageal cell lines OE33, SKGT-4, and OE21. RelA expression was assessed by immunohistochemical staining (n ϭ 97). The NF-B/RelA and IB protein expressions were also examined by Western blotting. Results: NF-B 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 ϭ 97) displayed NF-B immunoreactivity, and 87.5% of the NF-Bpositive tumors were Stage IIb and III compared with only 12.5% of patients with Stage I and IIa disease (P Ͻ 0.05). The expression of NF-B inversely correlated with major or complete pathologic responses to neoadjuvant chemotherapy and radiation therapy, with 15/20 (75%) responders in the NF-B-negative group compared with 7/38 (18%) in the NF-B-positive group (P Ͻ 0.00001). Moreover, incubation of esophageal cell lines OE33, SKGT-4, and OE21 with deoxycholic acid or low pH induced NF-B expression.

Molecular Pathways: Pathogenesis and Clinical Implications of Microbiome Alteration in Esophagitis and Barrett Esophagus

“…It is normally predominantly located in the cytoplasm, but translocates to the nucleus upon activation. While the normal esophagus has no detectable active NF-κB, high levels of active NF-κB are found in esophageal adenocarcinoma in the setting of reduced levels of IκB-α (a known inhibitor of NF-kB) (15). There is a stepwise increase in the activation of NF-κB pathway along the spectrum of reflux esophagitis (16–17), Barrett’s epithelium (18–19), and adenocarcinoma (16, 19–20), parallel to an increase in IL-1β, IL-6, IL-8, and TNF-α.…”

Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype

“…Epithelial Mesenchymal Transition (EMT) plays a key role in the metastasis of epithelial cancers through the involvement of various intracellular signalling pathways [24-26]. Loss of E-Cadherin is associated with EMT and tumour invasion [27] and has been linked functionally to NET1 and TGFβ [14].…”

Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction

“…NFκB is activated by acid and bile in EAC cell lines, possibly via production of reactive oxygen species, 166 , 168 , 169 and thereby provides evidence for over-activation of NFκB in the progression to EAC as a consequence of GERD. This is supported by recent data showing that bile induced activation of NFκB in non-dysplastic BE cells leads to apoptosis resistance in the face of concomitant bile-induced DNA damage 170 , 171 .…”

“…NFκB is located on chromosome 4, which is frequently amplified in Barrett carcinogenesis, 165 and is frequently expressed in the progression from BE to EAC 166 , 167 . NFκB is activated by acid and bile in EAC cell lines, possibly via production of reactive oxygen species, 166 , 168 , 169 and thereby provides evidence for over-activation of NFκB in the progression to EAC as a consequence of GERD.…”