Hoshi T, Sasano H, Kato K, Yabuki N, Ohara S, Konno R, Asaki S, Toyota T, Tateno H, Nagura H
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Anticancer Res. 1998 Nov-Dec;18(6A):4347-53.
Caspase3/CPP32 is a member of the interleukin-1 beta-converting enzyme (ICE) or cell death effector (CED)-3 family, which is involved in the induction of apoptosis and has been considered to be correlated with apoptosis because of the most downstream enzyme in their apoptosis inducing pathway. We immunolocalized Caspase3/CPP32 in both normal and neoplastic human gastric mucosa. We then correlated the findings with cell proliferation studied by Ki67 immunostaining and apoptosis, which was tested for by DNA fragmentation in situ using TdT-mediated dUTP biotin nick end labeling (TUNEL) method in order to examine possible biological significance in cell turnover of normal and pathological human gastric tissues. Caspase3/CPP32 immunoreactivity was detected in both the cytoplasm and nuclei of glandular epithelial cells, predominantly in the Ki67 positive proliferative zone and TUNEL positive foveolar epithelium of normal non-neoplastic gastric mucosa (n = 10) and tumor cells of both adenoma (n = 17) and carcinoma (n = 33). We determined the labeling index (LI) of Ki67, Caspase3/CPP32 and TUNEL positive cells by evaluating the number of positive cells in the same areas of serial tissue sections using computer-assisted image analysis. Ki67 LI in adenocarcinoma (78.6 +/- 12.6%) was significantly [p < 0.0001] higher than that of adenoma (43.8 +/- 8.9%) and non-neoplastic gastric mucosa (24.2 +/- 9.0%). Caspase3/CPP32 LI in adenocarcinoma (17.1 +/- 10.3%) was significantly lower [p < 0.0001] than that of gastric adenoma (33.1 +/- 19.8%) and non-neoplastic gastric mucosa (42.4 +/- 15.8%). TUNEL LI in adenocarcinoma (1.9 +/- 2.1%) was significantly [p < 0.0001] lower than that of non-neoplastic gastric mucosa (6.0 +/- 3.5%), but not significantly different from that of adenoma (3.0 +/- 2.9%). These results indicate that gastric adenocarcinoma is associated with an inhibition of apoptosis and the augmentation of proliferative activity of tumor cells compared to non-neoplastic gastric mucosa. There was a tendency to a positive correlation between the Caspase3/CPP32 and TUNEL LI and an inverse correlation between the Caspase3/CPP32 and Ki67 LI, when evaluating all the specimens, although the correlation did not reach statistical significance. These results also suggest that Caspase3/CPP32 is involved in the development or regulation of apoptotic cell death in cell turnover of normal and neoplastic mucosa of the human stomach.
半胱天冬酶3/CPP32是白细胞介素-1β转换酶（ICE）或细胞死亡效应蛋白（CED）-3家族的成员，参与细胞凋亡的诱导，由于其在细胞凋亡诱导途径中处于最下游，一直被认为与细胞凋亡相关。我们对正常和肿瘤性人类胃黏膜中的半胱天冬酶3/CPP32进行了免疫定位。然后，我们将这些发现与通过Ki67免疫染色研究的细胞增殖以及通过TdT介导的dUTP生物素缺口末端标记（TUNEL）法原位检测DNA片段化来检测的细胞凋亡相关联，以研究正常和病理性人类胃组织细胞更新中可能的生物学意义。在腺上皮细胞的细胞质和细胞核中均检测到半胱天冬酶3/CPP32免疫反应性，主要存在于正常非肿瘤性胃黏膜（n = 10）的Ki67阳性增殖区和TUNEL阳性小凹上皮以及腺瘤（n = 17）和癌（n = 33）的肿瘤细胞中。我们通过使用计算机辅助图像分析评估连续组织切片相同区域中的阳性细胞数量，确定了Ki67、半胱天冬酶3/CPP32和TUNEL阳性细胞的标记指数（LI）。腺癌中的Ki67 LI（78.6 +/- 12.6%）显著高于腺瘤（43.8 +/- 8.9%）和非肿瘤性胃黏膜（24.2 +/- 9.0%）[p < 0.0001]。腺癌中的半胱天冬酶3/CPP32 LI（17.1 +/- 10.3%）显著低于胃腺瘤（33.1 +/- 19.8%）和非肿瘤性胃黏膜（42.4 +/- 15.8%）[p < 0.0001]。腺癌中的TUNEL LI（1.9 +/- 2.1%）显著低于非肿瘤性胃黏膜（6.0 +/- 3.5%）[p < 0.0001]，但与腺瘤（3.0 +/- 2.9%）无显著差异。这些结果表明，与非肿瘤性胃黏膜相比，胃腺癌与肿瘤细胞凋亡的抑制和增殖活性的增强有关。在评估所有标本时，半胱天冬酶3/CPP32和TUNEL LI之间存在正相关趋势，半胱天冬酶3/CPP32和Ki67 LI之间存在负相关趋势，尽管这种相关性未达到统计学意义。这些结果还表明，半胱天冬酶3/CPP32参与人类胃正常和肿瘤性黏膜细胞更新中凋亡性细胞死亡的发生或调节。
