Sinicrope Frank A, Rego Rafaela L, Okumura Kenji, Foster Nathan R, O'Connell Michael J, Sargent Daniel J, Windschitl Harold E
Division of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Clin Cancer Res. 2008 Sep 15;14(18):5810-8. doi: 10.1158/1078-0432.CCR-07-5202.
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.
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.
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).
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.
仅含BH3结构域的促凋亡蛋白（Bim、Bad、Bid、Puma和Noxa）通过与抗凋亡Bcl-2蛋白上的调节位点结合来启动凋亡，直接中和其细胞保护功能。这些蛋白在结肠癌患者中的表达可能是复发率和生存率存在差异的原因。
对在基于5-氟尿嘧啶的辅助治疗试验中接受治疗的患者的存档肿瘤-淋巴结-转移分期II期和III期原发性结肠癌进行研究。使用组织微阵列（n = 431）对Bim, Puma和Noxa蛋白进行免疫组织化学分析。确定免疫评分并将其与临床病理变量、无病生存期（DFS）和总生存期（OS）率相关联。
在单变量分析中，肿瘤细胞质中促凋亡蛋白Bim（风险比，0.65；95%置信区间，0.44 - 0.97；P = 0.033）和Puma（风险比，0.59；95%置信区间，0.37 - 0.93；P = 0.022）的表达升高与更有利的总生存期显著相关，而Noxa蛋白则不然，并且Bim表达升高也与更好的无病生存期相关（P = 0.023）。患者年龄、肿瘤分期和组织学分级也是预后因素。多变量Cox分析表明，在调整组织学分级、肿瘤分期、年龄和治疗因素后，Bim（DFS，P = 0.030；OS，P = 0.045）和Puma（OS，P = 0.037）的表达是总生存期的独立预测因素。此外，Bim和Puma的联合变量对无病生存期（P = 0.0034）和总生存期（P = 0.0011）都具有高度判别力。
仅含BH3结构域的促凋亡蛋白Bim和Puma可以为接受基于5-氟尿嘧啶辅助化疗的II期和III期结肠癌患者提供预后信息。此外，我们的结果支持仅含BH3结构域的蛋白作为新型抗癌药物的分子靶点。
