大鼠肺癌侵袭转移中明胶酶A及其抑制剂的动态表达

目的探讨明胶酶A(MMP-2)及其抑制剂(TIMP-2)和DNA指数(DNA index,DI)在大鼠肺癌的发生和侵袭转移中的动态改变及其相互关系.方法用3-甲基胆蒽(MCA)及二乙基亚硝胺(DEN)碘油溶液在80只大鼠左肺叶支气管灌注诱发大鼠肺癌.以免疫组织化学S-P法和原位杂交技术,检测大鼠肺癌侵袭转移中MMP-2、TIMP-2的蛋白及mRNA表达,在Feulgen染色切片上利用图像分析系统测量DI值.结果随大鼠肺癌的发生发展,MMP-2和TIMP-2的阳性表达均逐渐增加,阳性率范围分别为8.5%～85.7%和6.4%～35.7%,DNA指数(DI值)亦逐渐增高(1.47±0.54)～(2.87±0.55)].MMP-2的表达在原位癌与早期癌、早期癌与转移癌之间差异具有显著性(P<0.05).肺癌与对照组和非癌性病变相比,MMP-2和TIMP-2表达的升高具有非常显著性(P<0.01).DI值的升高在原位癌与不典型增生之间差异具有显著性(P<0.05).大鼠肺癌癌变中TIMP-2的表达与MMP-2的表达呈负相关(P<0.05).MMP-2的表达与DNA异倍体呈正相关(P<0.01),并且MMP-2与大鼠肺癌晚期发生转移呈正相关.结论激活的MMP-2对基底膜(BM)等细胞外基质(ECM)的过度降解破坏,可能是诱发性肺癌侵袭转移的关键步骤.MMPs与TIMPs平衡状态的失衡可能在肺癌的发生及侵袭转移的生物学行为中起着重要作用.

Dynamic study on expression of gelatinase A and its natural inhibitor during invasion and metastasis of induced lung cancer in Wistar rats

OBJECTIVE: To investigate the dynamic expression and its relation of gelatinase A (MMP-2), its natural inhibitor (TIMP-2) and DNA index (DI) changes during carcinogenesis, invasion and metastasis in Wistar rats. METHODS: Squamous cell carcinoma of lung was induced with 3-methylcholanthrene (MCA) and diethyinitrosamine (DEN) in iodized oil by left intra-bronchial instillation in 80 Wistar rats. Immrno histochemistay (IHC) and in situ hybridigation were used in the monitor of MMP-2, TIMP-2 proteins and mRNA expression during invasion and metastasis of lung cancer in these rats, DNA index (DI) value was measured by guantitatove image analysis on feulgen stained sections. RESULTS: Along with the carcinogenis, the average poritive MNP-2 and TIMP-2 expressions increased, with positive rates of 8.5% - 85.7% and 6.4% - 35.7%. DI value also underwent the same changes (1.47 +/- 0.54) - (2.87 +/- 0.55). The difference of MMP-2 expression in carcinoma in situ versus early carcinoma and early carcinoma versus metastatic carcinoma are statistically significant (P < 0.05). Companing lung carcinome, the contrel group and non-cancerous lesions, the elevation of MNP-2 and TIMP-2 expressions were also sigmificant (P < 0.01). The DI elevation in carcinoma in situ and dysplasia were obviously significant (P < 0.05). Meanwhile a negative relation was noted in TINP-2 and MMP-2 expressions during carcinogenesis. There was a positive relation between MMP-2 expression and DNA poikiloidy (P < 0.01), which was related to the close relationship between MMP-2 and metastasis in advanced rat lung carcinoma (P < 0.05). CONCLUSION: The excess degradation and disruption of basement membranes by activated MMP-2 may be a key step in inducing lung cancer invasion and metastasis. The imbalance between MMP and TIMP may be a critical factor which affects biologic behavior of lung carcinogenesis, invasion and metastasis.