三氧化二砷联合热疗对大鼠肝脏移植瘤模型凋亡相关基因表达的影响

目的 研究三氧化二砷(arsenic trioxide,As₂O₃)联合热疗对大鼠肝脏移植瘤细胞的凋亡、热休克蛋白70(Heat shock protein 70,HSP70)、p53和增殖细胞核抗原(Proliferation cell nuclear antigen,PCNA)表达的影响,探讨其诱导肿瘤细胞凋亡的可能机制。方法 建立大鼠肝脏移植瘤模型,分别对荷瘤大鼠给予生理盐水、As₂O₃、热疗及As₂O₃联合热疗,观察肿瘤生长情况,用免疫组化法检测肿瘤细胞凋亡及肿瘤组织中HSP70、p53及PCNA的表达。结果 As₂O₃ 联合热疗的抗肿瘤作用最明显,坏死及凋亡细胞数量增加。对照组HSP70、p53及PCNA阳性细胞表达率分别为30.12%±3.60%,27.64%±4.90%和74.23%±6.35%,三氧化二砷联合热疗组HSP70、p53及PCNA阳性细胞表达率分别为87.4%1±5.70%,90.06%±6.42%和22.10%±6.17%。与对照组(仅给予As₂O₃或热疗处理)比较,经As₂O₃联合热疗处理后,HSP70、p53表达显著升高(P=0.000＜ 0.05),PCNA表达则显著降低(P=0.000 ＜0.05)。结论 As₂O₃与热疗联合应用治疗大鼠肝癌有明显的协同作用;As₂O₃联合热疗通过诱导HSP70及p53的表达和降低PCNA的表达抑制肝癌细胞增殖并促进细胞凋亡。

Expression of apoptosis related genes in liver cancer in rats induced by combined treatment of arsenic trioxide and hyperthermia

Objective To study the expression of heat shock proteins 70 （HSP70）, p53 and proliferation cell nuclear antigen（ PCNA）, and the mechanism of apoptosis induced by arsenic trioxide （As2 03 ）combined with hyperthermia in implanted liver cancer of rats. Methods The rat model of hepatocarcinoma was established and were randomly distributed into 4 groups including control group, which was treated with normal saline, As203 ther-apy group,which was treated with As203 at the concentration of 0.1% for 7d consecutively, hyperthermia group, which was treated with heat,and combination therapy group,which was treated with As2 03 combined with hyper- thermia. After those treatments, the apoptosis, the expression of heat shock proteins 70 （ HSP70）, p53 and the pro- liferation cell nuclear antigen（PCNA） in the cancer tissue were determined by histopathological examination and immuno - histochemical examination. Results The application of the combined treatment with As2 03 and hyper-thermia,which induced a large number of necrotic and apoptotic cells in the cancer tissue, showed significantly higher anticancer effect than the use of As2 03 or hyperthermia separately. The expression of HSP70, p53 and PCNA was 30.12% ±3.60% ,27.64% ±4.90% and 74.23% ±6.35% in the control group. The expression of HSP70,p53 and PCNA was 87.41%± 5.70% ,90.06% ± 6.42% and 22.10%±6. 17% in the group treated with the combination of As2O3 and hyperthermia. In the cancer tissue treated with the combination of As2O3 and hyperthermia, the expression of PCNA was significantly decreased （ P = 0.000 and P 〈 0.05 ） , while the expression of HSP70 and p53 was significantly increased （ P = 0.000 and P 〈 0.05 ）. Conclusion The results demonstrated that As2O3 and hyperthermia showed synergistic effect against liver cancer by inducing apoptosis and inhibiting the proliferation of cancer cells. These data implicated that the combination of As2O3 and hyperthermia could be an effective approach for the treatment of liver cancer.