Nuclear factor κ-light chain-enhancer of activated B cells is activated by radiotherapy and is prognostic for overall survival in patients with rectal cancer treated with preoperative fluorouracil-based chemoradiotheraphy.
OBJECTIVE
Rectal cancer is often clinically resistant to radiotherapy (RT) and identifying molecular markers to define the biologic basis for this phenomenon would be valuable. The nuclear factor κ-light chain-enhancer of activated B cells (NF-κB) is a potential anti-apoptotic transcription factor that has been associated with resistance to RT in model systems. The present study was designed to evaluate NF-κB activation in patients with rectal cancer undergoing chemoradiotherapy to determine whether NF-κB activity correlates with the outcome in rectal cancer patients.


METHODS
A total of 22 patients underwent biopsy at multiple points in a prospective study and the data from another 50 were analyzed retrospectively. The pretreatment tumor tissue was analyzed for multiple NF-κB subunits by immunohistochemistry. Serial tumor biopsy cores were analyzed for NF-κB-regulated gene expression using reverse transcriptase polymerase chain reaction and for NF-κB subunit nuclear localization using immunohistochemistry.


RESULTS
Several NF-κB target genes (Bcl-2, cellular inhibitor of apoptosis protein [cIAP]2, interleukin-8, and tumor necrosis factor receptor-associated-1) were significantly upregulated by a single fraction of RT at 24 h, demonstrating for the first time that NF-κB is activated by RT in human rectal tumors. The baseline NF-κB p50 nuclear expression did not correlate with the pathologic response to RT. However, an increasing baseline p50 level was prognostic for overall survival (hazard ratio, 2.15; p = .040).


CONCLUSIONS
NF-κB nuclear expression at baseline in rectal cancer was prognostic for overall survival but not predictive of the response to RT. Larger patient numbers are needed to assess the effect of NF-κB target gene upregulation on the response to RT. Our results suggest that NF-κB might play an important role in tumor metastasis but not to the resistance to chemoradiotherapy.
O'Neil
Bert H
BH
Department of Medicine, University of North Carolina, Chapel Hill, NC 27599-7305, USA.
Funkhouser
William K
WK
Calvo
Benjamin F
BF
Meyers
Michael O
MO
Kim
Hong Jin
HJ
Goldberg
Richard M
RM
Bernard
Stephen A
SA
Caskey
Laura
L
Deal
Allison M
AM
Wright
Fred
F
Baldwin
Albert S
AS
Tepper
Joel E
JE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D011836:Radiation Tolerance / Q000235:genetics*; D012004:Rectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000532:radiotherapy; D012189:Retrospective Studies; D047990:TNF Receptor-Associated Factor 1 / Q000235:genetics; D016896:Treatment Outcome
D051034:Inhibitor of Apoptosis Proteins; D016209:Interleukin-8; D016328:NF-kappa B; D009363:Neoplasm Proteins; D047990:TNF Receptor-Associated Factor 1