title: Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer.
abstract: BACKGROUND
  Lymphovascular invasion (LVI) and lymph node metastasis are conventional pathological factors associated with an unfavorable prognosis of urothelial carcinoma of the upper urinary tract (UC-UUT), but little is known about the molecular mechanisms underlying LVI and nodal metastasis in this disease. Rac1 small GTPase (Rac1) is essential for tumor metastasis. Activated GTP-bound Rac1 (Rac1 activity) plays a key role in activating downstream effectors known as Pak (21-activated kinase), which are key regulators of cytoskeletal remolding, cell motility, and cell proliferation, and thus have a role in both carcinogenesis and tumor invasion.
  
  
  METHODS
  We analyzed Rac1 activity and Pak1 protein expression in matched sets of tumor tissue, non-tumor tissue, and metastatic lymph node tissue obtained from the surgical specimens of 108 Japanese patients with UC-UUT.
  
  
  RESULTS
  Rac1 activity and Pak1 protein levels were higher in tumor tissue and metastatic lymph node tissue than in non-tumor tissue (both P < 0.0001). A high level of Rac1 activity and Pak1 protein expression in the primary tumor was related to poor differentiation (P < 0.05), muscle invasion (P < 0.01), LVI (P < 0.0001), and lymph node metastasis (P < 0.0001). Kaplan-Meier survival analysis showed that an increase of Rac1 activity and Pak1 protein was associated with a shorter disease-free survival time (P < 0.01) and shorter overall survival (P < 0.001). Cox proportional hazards analysis revealed that high Rac1 activity, Pak1 protein expression and LVI were independent prognostic factors for shorter overall and disease-free survival times (P < 0.01) on univariate analysis, although only Pak1 and LVI had an influence (P < 0.05) according to multivariate analysis.
  
  
  CONCLUSIONS
  These findings suggest that Rac1 activity and Pak1 are involved in LVI and lymph node metastasis of UC-UUT, and may be prognostic markers for this disease.
authors.affiliation: Department of Urology, Dokkyo Medical University, Mibu, Tochigi, Japan. kamait@dokkyomed.ac.jp
authors.forename: Takao
authors.initials: T
authors.lastname: Kamai
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Shirataki
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Furuya
authors.forename: Tsunehito
authors.initials: T
authors.lastname: Kambara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Abe
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Oyama
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000401:mortality / Q000556:secondary* / Q000628:therapy; D002454:Cell Differentiation; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000201:enzymology* / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D014571:Urologic Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D019459:Urothelium / Q000201:enzymology / Q000473:pathology; D054462:p21-Activated Kinases / Q000032:analysis*; D020830:rac1 GTP-Binding Protein / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C107953:RAC1 protein, human; C515903:PAK1 protein, human; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein