Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas
Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates.
Experimental Design: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil–based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates.
Results: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011).
Conclusions: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil–based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.
发布于 2008-09-22 22:16:45 修改
Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas
Purpose: Proapoptotic BH3-only proteins (Bim, Bad, Bid, Puma, and Noxa) initiate apoptosis by binding to regulatory sites on antiapoptotic Bcl-2 proteins, directly neutralizing their cytoprotective function. Expression of these proteins in colon cancer patients may account for differences in recurrence and survival rates.
Experimental Design: Archival tumor-node-metastasis stage II and III primary colon carcinomas from patients treated in 5-fluorouracil–based adjuvant therapy trials were studied. Immunohistochemical analysis of Bim, Puma, and Noxa proteins was done using tissue microarrays (n = 431). Immunoscores were determined and correlated with clinicopathologic variables and disease-free survival (DFS) and overall survival (OS) rates.
Results: Elevated expression of proapoptotic Bim (hazard ratio, 0.65; 95% confidence interval, 0.44-0.97; P = 0.033) and Puma (hazard ratio, 0.59; 95% confidence interval, 0.37-0.93; P = 0.022), but not Noxa, proteins in the tumor cytoplasm was significantly associated with more favorable OS in a univariate analysis, and elevated Bim expression was also associated with better DFS (P = 0.023). Patient age, tumor stage, and histologic grade were also prognostic. Multivariate Cox analysis showed that Bim (DFS, P = 0.030; OS, P = 0.045) and Puma (OS, P = 0.037) expression were independent predictors of OS after adjustment for histologic grade, tumor stage, age, and treatment. Furthermore, the combined variable of Bim and Puma was highly discriminant for both DFS (P = 0.0034) and OS (P = 0.0011).
Conclusions: The proapoptotic BH3-only proteins Bim and Puma can provide prognostic information for stage II and III colon cancer patients receiving 5-fluorouracil–based adjuvant chemotherapy. Furthermore, our results support BH3-only proteins as molecular targets of novel anticancer drugs.
人类结肠癌中Bim、Puma和Noxa表达的预后意义
目的：促凋亡基因BH3唯一蛋白（Bim、Bad、Puma和Noxa）通过结合抗凋亡基因Bcl-2蛋白的调控位点启动了凋亡，直接中和了它们的细胞保护功能。这些蛋白在结肠癌中的表达可能说明复发和转移率的差异。
实验设计：对采用5-Fu为基础的辅助治疗的，手术切除的TNM分期II和III期原发性结肠癌进行研究。应用组织微阵列技术和免疫组化技术检测了431例结肠癌中Bim、Puma和Noxa的表达。分析了他们的免疫积分的表达与临床病理参数、无疾病生存率（DFS）和总体生存率（OS）之间的关系。
结果：多因素分析显示促凋亡因子Bim（危害比0.65，95%可信区间为0.44-0.97）和Puma（危害比0.59，95%可信区间为0.37-0.93）的胞质表达水平高与较好的OS明显相关，而Noxa则没有这种相关性，Bim表达水平也与较好的DFS有关。病人年龄、肿瘤分期和组织学分级也与预后有关。多因素Cox分析显示在调整组织学分级、肿瘤分期、年龄和治疗后，Bim和Puma是OS的独立的预后因子。而且Bim和Puma结合变异在DFS和OS中具有高度的差异。
结论：促凋亡BH3唯一蛋白Bim和Puma能提供接受5-Fu为基础的辅助治疗的Ⅱ和Ⅲ期结肠癌病人的预后信息。而且，我们的结果支持BH3唯一蛋白可作为新的抗癌药物的分子靶点。
主题关键词标签(点击标签查看相关主题)：Bim Noxa Puma 表达 结肠癌 影响 预后