Predictive role of nuclear factor-kappaB activity in gastric cancer: a promising adjuvant approach with caffeic acid phenethyl ester.
BACKGROUND
The biologic significance of nuclear factor-kappaB (NF-kappaB) activation in human gastric cancer is unclear. We clarify the clinical significance of NF-kappaB activation and its relationship to Helicobacter pylori infection, a well-known pathogenesis of gastric cancer. Moreover, we examine the effects and underlying mechanisms induced by caffeic acid phenethyl ester (CAPE), an inhibitor of NF-kappaB, for gastric carcinoma.


METHODS
NF-kappaB was located immunohistochemically in 90 human gastric cancer specimens and 50 nonmalignant gastric specimens. The correlations between NF-kappaB activation, pathologic staging, and H. pylori infection were analyzed. We also performed electrophoretic mobility gel shift assay, real-time reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay to evaluate the responses of AGS (a gastric adenocarcinoma epithelial cell line) human gastric cancer cells subsequent to H. pylori infection or CAPE treatment.


RESULTS
Nuclear expression of NF-kappaB was significantly more frequently observed in gastric cancer tissues than in nonmalignant gastric tissues (31% vs. 4%, P=0.0001). The activity of NF-kappaB and the expressions of MMP-9, IL-1beta, and IL-8 in AGS cells were activated by H. pylori infection. However, the augmented responses could be significantly reversed by CAPE treatment. Moreover, in vitro studies showed that CAPE inhibits tumor growth and capacity for invasion.


CONCLUSIONS
NF-kappaB activation is related to carcinogenesis, tumor aggression, and H. pylori infection with the increased expression of MMP-9, IL-1beta, and IL-8. Moreover, NF-kappaB inhibitors or anti-inflammatory agents such as CAPE might be new adjuvant agent against invasive gastric carcinoma.
Wu
Cheng-Shyong
CS
Department of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Putz City, Chia-Yi Hsien, Taiwan. gi_cgmh@yahoo.com.tw
Chen
Miao-Fen
MF
Lee
I-Lin
IL
Tung
Shui-Yi
SY
D000230:Adenocarcinoma / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D002109:Caffeic Acids / Q000494:pharmacology*; D002278:Carcinoma in Situ / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D002470:Cell Survival; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D016481:Helicobacter Infections / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*
D002109:Caffeic Acids; D016328:NF-kappa B; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol