Increased Rac1 activity and Pak1 overexpression are associated with lymphovascular invasion and lymph node metastasis of upper urinary tract cancer

BMC Cancer. 2010 Apr 28;10:164. doi: 10.1186/1471-2407-10-164.


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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Blotting, Western
  • Carcinoma, Transitional Cell / enzymology*
  • Carcinoma, Transitional Cell / mortality
  • Carcinoma, Transitional Cell / secondary*
  • Carcinoma, Transitional Cell / therapy
  • Cell Differentiation
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Japan
  • Kaplan-Meier Estimate
  • Lymph Nodes / enzymology*
  • Lymph Nodes / pathology*
  • Lymphatic Metastasis
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Proportional Hazards Models
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Up-Regulation
  • Urologic Neoplasms / enzymology*
  • Urologic Neoplasms / mortality
  • Urologic Neoplasms / pathology*
  • Urologic Neoplasms / therapy
  • Urothelium / enzymology
  • Urothelium / pathology
  • p21-Activated Kinases / analysis*
  • rac1 GTP-Binding Protein / analysis*


  • Biomarkers, Tumor
  • RAC1 protein, human
  • PAK1 protein, human
  • p21-Activated Kinases
  • rac1 GTP-Binding Protein