Vav3 is a key modulator of GTP-hydrolases of the Rho/Rac family, which are crucially involved in cell proliferation. Vav3 is alternatively spliced in full-length Vav3-alpha and N-terminal truncated Vav3.1 lacking its self-regulatory domains. The aim of our study was to estimate the clinical impact of Vav3 and all other Vav family members in ovarian cancer. Purification of a stem-cell like side-population (SP) from ovarian cancer cell lines was performed by flow cytometry/FACS. Differences in gene expression between SP and NSP were assessed by Gene Array analysis and confirmed by RT-PCR and immunoblot. In addition, Vav mRNA expression was determined in 150 epithelial ovarian cancers. Clinicopathological parameters, platinum-sensitivity and survival were analyzed and associated with Vav expression. SP fractions of ovarian cancer cell lines exhibited marked overexpression of Vav3.1 (p < 0.001). Vav1 and Vav2 did not prove to be of clinicopathologic relevance in ovarian cancer. High Vav3.1 expression correlated with higher FIGO stage and residual disease. Furthermore, Vav3.1 overexpression was associated with poor progression-free (HR = 2.820, p = 0.0001) and overall survival (HR = 2.842, p = 0.0001). Subgroup analyses revealed an impact of Vav3.1 on survival in Type-II but not in Type-I cancers. Notably, platinum-refractory cancers showed marked overexpression of Vav3.1 compared to other subsets of platinum-sensitivity (15.848 vs. 6.653, p = 0.0001). In conclusion, Vav3.1 is over-expressed in stem-cell like SP fractions and is clinically relevant in the pathophysiology of ovarian cancer. The N-terminal truncated Vav3.1 may be decisively involved in mechanisms causing genuine multi-drug resistance.

Department of Biology and Biomedical Centre Faculty of Medicine Pilsen Charles University Prague 30100 Pilsen Czech Republic

Department of Dermatology Venereology and Allergology University Medical Center Mannheim Ruprecht Karl University of Heidelberg 68167 Mannheim Germany

Department of Obstetrics and Gynecology Medical University Innsbruck 6020 Innsbruck Austria

Division of Bioinformatics Biocenter Medical University Innsbruck 6020 Innsbruck Austria

Institute of Immunobiology Kantonsspital St Gallen 9007 St Gallen Switzerland

Institute of Legal Medicine Medical University Innsbruck 6020 Innsbruck Austria

Internal Medicine 5 Innsbruck Medical University 6020 Innsbruck Austria

Medical Clinic 3 Oncology Hematology Immunology and Rheumatology University Clinic Bonn 53127 Bonn Germany

Skin Cancer Unit German Cancer Research Center 69120 Heidelberg Germany

Tyrolean Cancer Research Institute 6020 Innsbruck Austria

Citace poskytuje Crossref.org

Evaluation of Vav3.1 as prognostic marker in endometrial cancer