Department of Surgery (Urology), University of Colorado, Aurora, Colorado 80045, USA.
Clin Cancer Res. 2013 Jun 1;19(11):2850-60. doi: 10.1158/1078-0432.CCR-12-3084. Epub 2013 Apr 10.
Discovery transcriptomic analyses suggest eukaryotic initiation factor 3b (eIF3b) is elevated in human bladder and prostate cancer, yet its role as a prognostic factor or its requirement in the maintenance or progression of human cancer is not established. Here, we determine the therapeutic potential of eIF3b by examining the clinical relevance of its expression in human cancer tissues and its role in experimental tumor models.
We examined mRNA expression of eIF3b in bladder (N = 317) and prostate (N = 566) tissue samples and protein expression by immunohistochemistry in 143 bladder tumor samples as a function of clinicopathologic features. The impact of eIF3b depletion by siRNA in human cancer lines was evaluated in regard to in vitro cell growth, cell cycle, migration, in vivo subcutaneous tumor growth, and lung colonization.
eIF3b mRNA expression correlated to tumor grade, stage, and survival in human bladder and prostate cancer. eIF3b protein expression stratified survival in human bladder cancer. eIF3b depletion reduced in vitro cancer cell growth; inhibited G1-S cell-cycle transition by changing protein but not RNA expression of cyclin A, E, Rb, and p27Kip1; inhibited migration; and disrupted actin cytoskeleton and focal adhesions. These changes were associated with decreased protein expression of integrin α5. Integrin α5 depletion phenocopied effects observed with eIF3b. eIF3b-depleted bladder cancer cells formed fewer subcutaneous tumors that grew more slowly and had reduced lung colonization.
eIF3b expression relates to human bladder and prostate cancer prognosis, is required for tumor growth, and thus a candidate therapeutic target.
发现转录组分析表明，真核起始因子 3b（eIF3b）在人类膀胱癌和前列腺癌中升高，但作为预后因素的作用及其在人类癌症的维持或进展中的必要性尚未确定。在这里，我们通过检查其在人类癌症组织中的表达的临床相关性及其在实验肿瘤模型中的作用来确定 eIF3b 的治疗潜力。
我们检查了膀胱癌（N=317）和前列腺癌（N=566）组织样本中 eIF3b 的 mRNA 表达，并通过免疫组织化学在 143 个膀胱癌样本中检查其蛋白表达与临床病理特征的关系。通过 siRNA 耗竭 eIF3b 对人癌细胞系的影响进行了评估，包括体外细胞生长、细胞周期、迁移、体内皮下肿瘤生长和肺定植。
eIF3b mRNA 表达与人类膀胱癌和前列腺癌的肿瘤分级、分期和生存相关。eIF3b 蛋白表达在人类膀胱癌中分层了生存。eIF3b 耗竭减少了体外癌细胞生长；通过改变细胞周期蛋白 A、E、Rb 和 p27Kip1 的蛋白而不是 RNA 表达，抑制了 G1-S 细胞周期转换；抑制迁移；并破坏了肌动蛋白细胞骨架和焦点粘连。这些变化与整合素 α5 蛋白表达的降低有关。整合素 α5 耗竭模拟了用 eIF3b 观察到的作用。eIF3b 耗竭的膀胱癌细胞形成的皮下肿瘤更少，生长更慢，肺定植减少。
eIF3b 表达与人类膀胱癌和前列腺癌的预后有关，是肿瘤生长所必需的，因此是一个候选治疗靶点。
