Caspase-3 expression in human gastric carcinoma and its clinical significance.
OBJECTIVE
Caspase-3 is one of the most important molecules in the apoptosis cascade, and the relationship between caspase-3 expression and prognosis has been reported in many types of malignancies. However, the involvement of caspase-3 in human gastric carcinoma is not fully understood. We evaluated caspase-3 expression in human gastric carcinoma to clarify the clinicopathological importance and investigated the apoptosis avoidance mechanism by an immunohistological method.


METHODS
Specimens from 151 patients who underwent gastrectomy at the Department of Surgery and Surgical Basic Science of Kyoto University Hospital were investigated. Caspase-3 expression in cancer cells was evaluated by comparing its expression in the germinal center of the lymphoid follicle, and was quantified as the caspase-3 expression index (C3EI). C3EI was compared with the expression of Bcl-2 and the TdT-mediated dUTP biotin nick-end labeling (TUNEL) in 80 randomly selected cases. Actual activation of caspase-3 was determined by immunohistochemistry using monoclonal antibody that recognizes only activated caspase-3.


RESULTS
C3EI correlated significantly with lymph node metastasis (negative 105.5-78.7, positive 153.8 +/- 66.1 p = 0.001) and the lower C3EI group had a better prognosis than the higher group (log-rank test, p = 0.0001). Cox multivariate analysis showed that age, operation curability, tumor invasion and C3EI were significant independent determinants of overall survival. Bcl-2 and TUNEL staining had no significant correlations with C3EI. Immunohistochemistry of activated caspase-3 revealed that most caspase-3 in gastric cancer cells was not activated, in accordance with TUNEL assay.


CONCLUSIONS
Our results show that C3EI is a novel, independent prognostic factor in gastric cancer patients and cancer cells may avoid apoptosis by inhibiting caspase-3 activation.
Isobe
Naoki
N
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan. isobe@kuhp.kyoto-u.ac.jp
Onodera
Hisashi
H
Mori
Akira
A
Shimada
Yutaka
Y
Yang
Weige
W
Yasuda
Seiichi
S
Fujimoto
Akihisa
A
Ooe
Hideaki
H
Arii
Shigeki
S
Kitaichi
Masanori
M
Imamura
Masayuki
M
D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D053148:Caspase 3; D020169:Caspases / Q000032:analysis*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D010784:Photomicrography; D011237:Predictive Value of Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013274:Stomach Neoplasms / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology* / Q000601:surgery; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D019253:Proto-Oncogene Proteins c-bcl-2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases