肝细胞癌患者内质网应激-凋亡信号通路的性别差异

Gender difference in endoplasmic reticulum stress and apoptosis signals in patients with hepatocellular carcinoma

目的:评估内质网应激-凋亡信号通路与肝细胞癌患者性别的相关性。方法:回顾分析肝细胞癌术后病例,随机抽取男性及女性患者各40例手术切除的肝癌组织标本,同时纳入10例肝血管瘤手术切除的标本作为对照。蛋白质印迹法检测手术标本内质网应激-凋亡信号通路各蛋白的表达量。分析年龄、性别、TNM分期、Child分级、肿瘤分化程度以及是否合并乙型肝炎、肝硬化与内质网应激-凋亡通路蛋白表达的相关性。结果:肝细胞癌组织内包括葡萄糖调节蛋白78(GRP78),GRP94,剪切型X盒结合蛋白1(spliced X-box binding protein 1,s XBP1),I型内质网跨膜激酶(type-I ER transmembrane protein kinase,IRE1α),转录激活因子-6(activating transcription factor-6(ATF-6),C/EBP同源蛋白(C/EBP homologous protein,CHOP)和Caspas3的内质网应激及凋亡信号均明显强于对照组(均P<0.05)。年龄、分期、是否合并肝炎、肝硬化以及Child分级因素对肝细胞癌组织内质网应激信号无明显影响。与女性患者相比,男性病例包括s XBP1,ATF-6,CHOP和Caspase3的内质网应激-凋亡信号显著增强(均P<0.05);与中、高分化组比较,低分化组ATF-6的表达明显下降(均P<0.05)。但进一步分层分析结果显示,分化程度对内质网应激信号ATF-6无明显影响。结论:男性病例肝细胞癌组织内质网应激-凋亡信号比女性病例明显增强。

Objective： To investigate the effect of gender on endoplasmic reticulum-stress（ER-stress）and apoptosis signals in patients with hepatocellular carcinoma. Methods ： Clinical data was collected and retrospectively analyzed from 80 routine hepatocellular carcinoma （ HCC ） patients, including 40 male and 40 female. Normal liver parenchymal tissues were obtained as controls from 10 Chinese patients with hemangioma. The clinical typing of tumors was determined according to the TNM classification system.The histological grade of tumor differentiation was evaluated by the Edmondson grading system and liver function was assessed by Child-Pugh score system. Characteristics of ER-stress and apoptosis signal in patients and controls were analyzed by Western blotting. Results ： The levels of ER-stress signal factors including glucose regulated protein 78 （ GRP78 ） , GRP94 , spliced X box-binding protein 1 （ sXBPl ） , activating transcription factor 6 （ATF-6） , inositol requiring enzyme 1 （IREla） , C/EBP homologous protein （CHOP） were elevated significantly compared with control （ P 〈 0. 05 ） . Meanwhile, the level of Caspase3 was increased in HCC patients. The clinic features,such as stage, HBV infection, liver cirrhosis and Child grade had on obvious effect on ER-stress signal. Only had age affected on GRP78 levels rather than other ER-stress signal factors. Interestingly, the levels of sXBPl, ATF6 , CHOP and Caspase3 ele-vated significantly, while GRP78 level reduced in male patients compared with those of the female（P 〈 0. 05 ） . ATF6 was also reduced significantly in poorly-differentiated patients （P 〈0.05）. Further studies indicated that differentiation had no effect on ER-stress and apoptosis signals. Conclusion; ER-stress and apoptosis signals were induced and GRP78 level was increased in male HCC patients. These results provided a preliminary data for personalized therapy based on gender.