摘要目的 研究BH3-only蛋白家族中p53上调凋亡调控因子(PUMA)和与bcl-2相互作用的细胞死亡调解因子(BIM)在结直肠癌组织中的表达及其与结直肠癌侵袭、转移和预后关系.方法 采用免疫组化染色方法(EnVision),检测PUMA和BIM蛋白在30例正常大肠黏膜、30例大肠腺瘤及142例结直肠癌组织中的表达.分析PUMA、BIM蛋白表达与患者临床病理特征、预后及化疗耐药相关蛋白[P-糖蛋白(P-gp)、谷胱甘肽S转移酶-π(GST-π)]的相关性.结果 PUMA蛋白在结直肠癌组织中的阳性表达率为82.4％,低于其在大肠腺瘤和正常大肠黏膜组织中的阳性表达率(均为96.7％)(x2=3.93、3.93,P＜0.05).BIM蛋白在结直肠癌组织中的阳性表达率为62.7％,明显低于其在大肠腺瘤组织中和正常大肠黏膜的阳性表达率(90.0％和96.7％)(x2 =8.42、13.29,P＜0.01).PUMA蛋白与BIM蛋白在结直肠癌组织中的表达呈正相关(r=0.747,P=0.000).PUMA蛋白的表达与肿瘤的分化程度(x2 =11.87)、浸润深度(x2=11.59)、淋巴结转移(x2=12.82)、TNM分期(x2=33.47)以及P-gp表达(x2=18.30)有关(P＜0.05),而与患者的年龄、性别、肿瘤大小、病理组织学类型以及GST-π表达无关(P＞0.05).BIM蛋白的表达与分化程度(x2=16.19)、淋巴结转移(x2=14.95)、TNM分期(x2=52.66)以及P-gp表达(x2 =10.60)有关(P＜0.05),而与患者的年龄、性别、肿瘤大小、浸润深度、病理组织学类型以及GST-π表达无关(P＞0.05).PUMA、BIM阳性表达者的术后1、3、5年生存率明显高于阴性表达者(x2=6.10、27.60,P＜0.05).淋巴结转移(RR=0.238)、TNM分期(RR=7.895)、PUMA(RR=1.691)和BIM蛋白的表达(RR =0.440)可作为结直肠癌独立的预后指标(P＜0.05).结论 PUMA、BIM在结直肠癌中的表达与结直肠癌的侵袭、转移和预后明显相关.PUMA和BIM蛋白表达降低的结直肠癌患者病期晚、预后差.

abstractsObjective To study p53 up-regulated modulator of apoptosis (PUMA) and bcl-2 interacting mediator of cell death (BIM) of the BH3-only protein family expression in colorectal cancer tissues and its relationship with colorectal cancer invasion,metastasis and prognosis.Methods Immunohistochemical staining (EnVision) was used to detect PUMA/BIM expression in 30 cases of normal mucosa,30 cases of colorectal adenoma and l42 cases of colorectal cancer tissues.Results PUMA in colorectal cancer tissues was positive expressed (82.4％),which was significantly lower than in the normal mucosa colorectal adenomas (96.7％) and normal mucosa tissues (96.7％) (both x2 =3.93,P ＜ 0.05).Positive expression rate of BIM in colorectal cancer tissues (62.7％) was significantly lower than that in colorectal adenomas and normal mucosa (96.7％ and 90.0％) (x2 =8.42 and 13.29,P ＜0.01).PUMA and BIM in colorectal cancer tissues were positively correlated (r =0.747,P =0.000).PUMA expression was related to tumor differentiation (x2 =11.87),invasion depth (x2 =11.59),lymph node metastasis (x2 =12.82),TNM stage (x2 =33.47) and P-gp expression (x2 =18.30),all P ＜ 0.05,but not related to the patients' age,gender,tumor size,tumor histological type and GST-π expression (P ＞ 0.05).BIM expression was related to tumor differentiation (x2 =16.19),lymph node metastasis (x2 =14.95),TNM stage (X2 =52.66) and P-gp expression (x2 =10.60) (P ＜0.05),but not related to patients' age,sex,tumor size,tumor histological type,invasion depth and GST-π expression (P ＞ 0.05).1-,3-,5-year survival rates of the positive expression of PUMA/BIM in patients with colorectal cancer were significantly higher than that of PUMA/BIM in patients with negative expression (x2 =6.10 and 27.6,P ＜0.05).Cox multivariate analysis showed that lymph node metastasis (RR =0.238),TNM stage (RR =7.895),PUMA (RR =1.691) and BIM (RR =0.440) could be used as independent prognostic indicators (P ＜ 0.05).Conclusions PUMA and BIM expressions in colorectal cancer are related to the tumor invasion,metastasis and prognosis.Low expressions of PUMA and BIM were related to the late period and poor prognosis of colorectal cancer patients.