Journal List > Tuberc Respir Dis > v.63(3) > 1001139

Shin, Lee, and Park: Expression of Caspase 3, Survivin, and p53 Protein in Urethane Induced Mouse Lung Carcinogenesis



An imbalance of cell proliferation and cell apoptosis is an important mechanism in carcinogenesis. Capase 3, survivin and p53 have been identified as important members of the apoptotic related proteins. This study evaluated the proliferating cell nuclear antigen(PCNA), apoptosis, apoptotic related protein such as capase 3, survivin and p53 using urethane-induced mouse lung carcinogenesis, which provides reproducible steps from hyperplasia to adenocarcinoma.


Urethane was administered to the ICR mice through an intra-peritoneal injection, The mice were sacrificed at 5, 15, and 25 weeks after urethane intervention. The sequential morphological changes and immunohistochemical expression of PCNA, apoptosis, capase 3, survivin, and p53 were examined during mouse lung carcinogenesis.


During carcinogenesis, the sequential histological changes were observed from hyperplasia of type II pneumocytes, to anadenoma, and ultimately to an overt adenocarcinoma. The PCNA Labeling index (LI) was 9.6% in hyperplasia, 23.2% in adenoma, and 55.7% in adenocarcinoma, respectively. The apoptotic LI was 0.24% in hyperplasia, 1.25% in adenoma, and 5.27% in adenocarcinoma. A good correlation was observed between the PCNA LI and apoptotic LI. The expression of caspase 3 was remarkable- i.e., 46.7% in adenocarcinoma, in contrast to 15% in hyperplasia and 16% in adenoma. Survivin was detected weakly in the alveolar hyperplasia and showed an increasing expressional pattern in adenoma and adenocarcinoma. p53 expression was detected only in the adenocarcinoma lesions with an expression rate of 13.3%. The level of caspase 3 expression correlated with the increase in the apoptotic index. The positive expression of caspase 3 was associated with an increased apoptotic index.


These results suggest that the PCNA LI and apoptotic LI might be useful markers for evaluating the risk of a malignant transformation. In addition, caspase, survivin and p53 might play a role in the early and late steges of urethane-induced mouse lung carcinogenesis.

Figures and Tables

Figure 1
A. Gross finding of urethane-induced lungs, which shows multiple masses. B, C. Sequential change in urethane-induced lung lesions, showing adenoma (Figure 1B) and infiltrating adenocarcinoma (Figure 1C)(Hematoxylline & Eosin Stain, ×200). D. Immunohistochemical reactivity for PCNA in adenoma (×200). E. TUNNEL stain shows occasional nuclear staining in adenocarcinoma of lung (×200). F, G, H. Immunohistochemical reactivity for capase 3 (Figure 1F), p53 (Figure 1G) and survivin protein (Figure 1H) showing positive cytoplasmic staining (×200).
Table 1
Histologic changes of the lung in mice treated with urethane

Tumor multiplicity; Number of tumor per mouse.

Table 2
PCNA and apoptotic labeling index of the mice lung lesions during urethane-induced carcinogenesis

Significantly greater than the other groups, p<0.01.

Table 3
Expression rates of caspase-3, survivin and p53 protein in mouse lung lesions by urethane-induced lung carcinogenesis

NS: not significantly different.

Table 4
Proliferation and apoptotic index according to caspase 3 and survivin expressin expression

n: number of tumor lesion; NS: not significantly different. Significantly greater than the other groups, p<0.01.


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