Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer.
OBJECTIVE
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
Rho/ROCK pathway apparently involved in occurrence and progression of bladder cancer may be valuable prognostic markers.
Kamai
Takao
T
Department of Urology, Dokkyo University School of Medicine, Tochigi 321-0293, Japan. kamait@dokkyomed.ac.jp
Tsujii
Toshihiko
T
Arai
Kyoko
K
Takagi
Kentaro
K
Asami
Hidekazu
H
Ito
Yuji
Y
Oshima
Hiroyuki
H
D000199:Actins / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D012044:Regression Analysis; D013997:Time Factors; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
D000199:Actins; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein