Expression Of Survivin And Effect Of As₂O₃ On It In Transitional Cell Carcinoma Of Bladder

Introduction and ObjectiveBladder cancer is the most common cancer in urinary surgery in china, usually originate from transitional epithelia, about 80% of the tumor is superficial tumor. After surgery treatment, about 70-80% of the superficial tumor recur and there is 20-30% of it progress to muscle-invasive or metastatic disease. 50% of the patients with initial and recurring invasive tumor will metastasize in 2 years and 60% of them will die in 5 years. It is the important goal for urologist to find the reasonable method with which the bladder cancer can be diagnosed and treated in time in order to increase the survival rate. Urologist are searching sensitive, specific, convenient, economic, non-invasive marker for prediction of prognosis in bladder cancer.Now people find that apoptosis play an important role in carcinogenesis and cancer porgession and investigate the suppression of apoptosis in bladder cancer in order to diagnosis and treat bladder cancer by method that promote cancer cell apoptosis. The inhibitor of apoptosis proteins(IAPs) are a family of antiapoptotic proteins that bind and inhibit caspases 3, 7, and/or 9, but not caspase 8. Growing evidence also indicates that IAPs also modulate cell division, cell cycle progression, and signal transduction pathways. As our basic understanding of IAPs has increased, the knowledge is being translated into clinically useful applications in the diagnosis and treatment of malignancy. For example, IAPs such as survivin are being investigated as diagonstic markers for the presence of occult malignancy. In addition, IAPs overexpression is a poor prognostic marker in a variety of solid tumors and hematologic malignancies. Finally, IAPs are attractive therapeutic targets, and efforts are under way to develop antisense and chemical IAP inhibitors that may be useful for the treatmeng of a variety of malignancies. For all of these potential clinical applications, however, the challenge remains to incorporate these findings into actual clinical practice.At a fundamental level, cancer fails to respond to treatment because the malignant cells fail to die in response to chemotherapy, radiation, or the immune surveillance by endogenous cytotoxic T cells and natural killer cells. In part, the failure of cell death is due to failure of the apoptosis and caspase activation pathways, Many anti-cancer agent work by the induction of apoptosis, recently, As₂O₃(arsenic trioxide) have been used to treat acute promyelocytic leukemia (APL). The mechanisms of action were shown to be associated with the induction of apoptosis and differentiation. Some studies revealed that As₂O₃ could trigger apoptosis of some solid tumor cells, this suggests that As₂O₃ may be active against a wide variety of human tumors, but the mechanisms of are not completely understood.In this study, we try to make clear the relationship between the expression of survivin in transitional cell carcinoma of bladder and tumor stage ,grade, and find out the possible mechanism between As₂O₃ activity and corresponding change of survivin in BIU-87 cells. Our cellular model may help to reveal molecular events in relation to apoptosis by As₂O₃ in bladder cancer, it is profound significant in tumor treatment and diagnosis.Method1. we use immunohistochemistry methed to measure the expression of survivin in 72 patients with bladder transitional cell carcinoma ,and examine the association between survivin expression and grade,tumor stage and various clinicopathological characteristics. 2. The BIU-87 cells were treated by various concentration of As₂O₃ for different period and the proliferation activity of BIU-87 cells were tested by MTT assay, expression of survivin and cell cycle were detected by flow cytometry after BIU-87 cells were treated with various concentration of As₂O₃.ResultsOf the 72 patients, 47.2% exhibited markedly survivin immunoreactivities in tumor cells than in the normal transitional epithelia and survivin mainly lie in cytoplasm. Patients exhibited much higher survivin expression in T_2～4 (62.5%) than in T_is～1 (35.0%) ( P<0.05 ). survivin was much positively expressed in poor differentiation bladder cancer G₃(80.0%) than in good differentiation bladder cancer G₂ (46.9%),G₁ (28.0%) (P<0.05 ).No significant correlation was found among survivin expression level, patient age, sex.After treated with As₂O₃,the proliferation activity of BIU-87 cells were significantly slowed down compare to the control group,with an evident time and dose-response relationship. ( P<0.05 ) .The percentage of BIU-87 cells in subG₀/G₁ and G₀/G₁ phase is 12.30%,86.58% respectively,higher than that in control group which is 1.25% and 65.52%, respectively (P<0.05 ), As₂O₃ can induce the apoptosis of BIU-87 cells with concentration dependent. After cultured with As₂O₃ the expression of survivin was downregulated significantly,which were concentration dependent.Conclusion1. survivin was positively expressed in bladder cancer cells and negatively expressed in the normal transitional epithelia.2.The expression of survivin has significant relationship to tumor stage, survivin was much positively expressed in invasive tumor than in superficial bladder cancer.3.The expression of survivin has significant relationship to differentiation, survivin was much positively expressed in poor differentiation bladder cancer than in good differentiation bladder cancer.4. As₂O₃ can significantly decrease cell viability of BIU-87 cells with an time and dose-response relationship.5. As₂O₃ can significantly induce the apoptosis of BIU-87 cells,and can lead to reduction expression of survivin ,which were concentration dependent.