IL-6通过激活HIF-1α促进人胃癌MKN45细胞裸鼠移植瘤顺铂耐药的作用及机制研究

IL-6-mediated HIF-1α Activation Promotes the Resistance of Gastric Cancer Transplanted Tumors to Cisplatin in BALB/c Nude Mice

目的 探讨IL-6介导的HIF-1α激活对人胃癌MKN45细胞裸鼠移植瘤顺铂耐药的影响。方法 通过接种人胃癌MKN45细胞建立人胃癌裸鼠移植瘤模型。将胃癌移植瘤裸鼠分为三组:对照组,顺铂组和顺铂+IL-6组,每组10只。给药4周后,取出瘤体测量瘤重及抑瘤率,并用Western-blot法检测肿瘤组织中相关蛋白的表达。结果 在瘤重方面,对照组>顺铂+IL-6组>顺铂组;在抑瘤率方面,顺铂组>顺铂+IL-6组,差异有统计学意义(P<0.05)。进一步研究发现IL-6诱导裸鼠移植瘤耐药主要通过激活HIF-1α,抑制下游凋亡通路(Bax,Bcl-2, Cleaved Caspase-9及Cleaved Caspase-3)的激活及诱导下游药物外排通路(P-gp和MRP1)的表达(P<0.05)。结论 IL-6干预可促进人胃癌MKN45细胞裸鼠移植瘤顺铂耐药,其机制主要通过激活HIF-1α及下游信号通路。

Objective To investigate the effect of IL-6/HIF-1α activation on resistance to cisplatin in nude mice with subcutaneous xenograft of human gastric cancer MKN45 cells.Methods Human gastric cancer transplanted tumor models were established by injection of MKN45 cells on BALB /c nude mice.Transplanted tumor models were divided into three groups,the control group,cisplatin-treated group,and cisplatin/IL-6-treated group,with 10 mice for each.After 4-week treatment,the transplanted tumor weight was measured and tumor-inhibition rate were calculated.The expressions of related proteins were examined by western blot analysis.Results It was revealed that the weight of tumors was control group>cisplatin/IL-6-treated group>cisplatin-treated group (P<0.05).The tumor-inhibition rate of cisplatin/IL-6-treated group was significantly lower than that of cisplatin-treated group (P<0.05).Moreover,IL-6 mediated resistance of human gastric cancer transplanted tumors to cisplatin was induced by activating HIF-1α,inhibiting cell apoptotic pathway (Bax,Bcl-2,Cleaved Caspase-3 and Cleaved Caspase-9),and inducing drug efflux pathway (P-gp and MRP1).Conclusion IL-6 treatment promoted resistance of human gastric cancer transplanted tumors to cisplatin by inducing HIF-1α activation and affecting downstream signaling pathways.