Kamai Takao, Tsujii Toshihiko, Arai Kyoko, Takagi Kentaro, Asami Hidekazu, Ito Yuji, Oshima Hiroyuki
Department of Urology, Dokkyo University School of Medicine, Tochigi 321-0293, Japan.
Clin Cancer Res. 2003 Jul;9(7):2632-41.
The small GTP-binding protein Rho and its best-characterized downstream effector Rho-associated serine-threonine protein kinase, ROCK, participate in actin cytoskeleton organization, and are linked to pathogenesis and progression of several human tumors. We investigated the roles of Rho and ROCK in bladder cancer.
Using Western blotting, we quantitated Rho and ROCK protein expression in paired tumor and nontumor surgical samples from 107 consecutive Japanese patients with bladder cancer.
RhoA, RhoC, and ROCK were more abundant in tumors and metastatic lymph nodes than in nontumor bladder and uninvolved lymph nodes (P < 0.0001). Amounts of RhoA and RhoC protein, and ROCK protein expression correlated positively with one another (P < 0.0001). High RhoA, RhoC, and ROCK expression were related to poor tumor differentiation (P < 0.05, P < 0.01, and P < 0.01, respectively), muscle invasion (P < 0.001), and lymph node metastasis (P < 0.05). Kaplan-Meier plots linked high RhoA, RhoC, and ROCK protein expression to shortened disease-free and overall survival (P < 0.0001). By univariate analysis, high RhoA, RhoC, and ROCK protein expression predicted shortened disease-free and overall survival (P < 0.0001). By multivariate analysis, only RhoC was independently influenced in disease-free survival (P < 0.05), and RhoA and RhoC in overall survival (P < 0.001). In contrast, RhoB expression was inversely related to the grade and stage (P < 0.05), and its higher expression is associated with better overall survival (P < 0.05). In superficial tumors (Ta or T1; 63 patients), RhoA, RhoC, and ROCK were unrelated with recurrence-free survival. Overall survival in tumors invading muscle (T2 to T4; 44 patients) was significantly influenced by RhoA, RhoC, and ROCK in a Kaplan-Meier analysis (P < 0.0001, P < 0.0001, and P < 0.01, respectively). Whereas RhoA, RhoC, and ROCK independently predicted shortened overall survival in patients with invasive tumor by univariate analysis (P < 0.0001, P < 0.0001, and P < 0.01, respectively), only RhoC did so by multivariate analysis (P < 0.05).
Rho/ROCK pathway apparently involved in occurrence and progression of bladder cancer may be valuable prognostic markers.
小GTP结合蛋白Rho及其特征最明确的下游效应分子Rho相关丝氨酸 - 苏氨酸蛋白激酶（ROCK）参与肌动蛋白细胞骨架的组织，并与多种人类肿瘤的发病机制和进展相关。我们研究了Rho和ROCK在膀胱癌中的作用。
我们采用蛋白质印迹法，对107例连续的日本膀胱癌患者手术切除的配对肿瘤和非肿瘤样本中的Rho和ROCK蛋白表达进行定量分析。
RhoA、RhoC和ROCK在肿瘤组织和转移淋巴结中的表达量高于非肿瘤膀胱组织和未受累淋巴结（P < 0.0001）。RhoA和RhoC蛋白的表达量以及ROCK蛋白表达量之间呈正相关（P < 0.0001）。RhoA、RhoC和ROCK的高表达与肿瘤低分化相关（分别为P < 0.05、P < 0.01和P < 0.01）、肌肉浸润（P < 0.001）以及淋巴结转移（P < 0.05）。Kaplan - Meier生存曲线分析显示，RhoA、RhoC和ROCK的高表达与无病生存期和总生存期缩短相关（P < 0.0001）。单因素分析显示，RhoA、RhoC和ROCK的高表达预示着无病生存期和总生存期缩短（P < 0.0001）。多因素分析显示，仅RhoC对无病生存期有独立影响（P < 0.05），RhoA和RhoC对总生存期有独立影响（P < 0.001）。相反，RhoB的表达与肿瘤分级和分期呈负相关（P < 0.05），其高表达与较好的总生存期相关（P < 0.05）。在浅表性肿瘤（Ta或T1；63例患者）中，RhoA、RhoC和ROCK与无复发生存期无关。在侵犯肌肉的肿瘤（T2至T4；44例患者）中，Kaplan - Meier分析显示RhoA、RhoC和ROCK对总生存期有显著影响（分别为P < 0.0001、P < 0.0001和P < 0.01）。单因素分析显示，RhoA、RhoC和ROCK独立预测浸润性肿瘤患者总生存期缩短（分别为P < 0.0001、P < 0.0001和P < 0.01），多因素分析显示仅RhoC有此作用（P < 0.05）。
Rho/ROCK信号通路明显参与膀胱癌的发生和发展，可能是有价值的预后标志物。
