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4 záznamů v Medvik Filtry

Článek

Truncated isoform Vav3.1 is highly expressed in ovarian cancer stem cells and clinically relevant in predicting prognosis and platinum-response

Reimer, Daniel
Autor Reimer, Daniel Department of Obstetrics and Gynecology, Medical University Innsbruck, 6020, Innsbruck, Austria
Boesch, Maximilian
Autor Boesch, Maximilian Institute of Immunobiology, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland. Internal Medicine V, Innsbruck Medical University, 6020, Innsbruck, Austria. Tyrolean Cancer Research Institute, 6020, Innsbruck, Austria
Wolf, Dominik
Autor Wolf, Dominik Internal Medicine V, Innsbruck Medical University, 6020, Innsbruck, Austria. Medical Clinic 3, Oncology, Hematology, Immunology and Rheumatology, University Clinic Bonn (UKB), 53127, Bonn, Germany
Marth, Christian
Autor Marth, Christian Department of Obstetrics and Gynecology, Medical University Innsbruck, 6020, Innsbruck, Austria
Sopper, Sieghart
Autor Sopper, Sieghart Internal Medicine V, Innsbruck Medical University, 6020, Innsbruck, Austria. Tyrolean Cancer Research Institute, 6020, Innsbruck, Austria
Hatina, Jiri
Autor Hatina, Jiri Department of Biology and Biomedical Centre, Faculty of Medicine Pilsen, Charles University Prague, 30100, Pilsen, Czech Republic
Altevogt, Peter
Autor Altevogt, Peter Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167, Mannheim, Germany
Parson, Walther
Autor Parson, Walther Institute of Legal Medicine, Medical University Innsbruck, 6020, Innsbruck, Austria
Hackl, Hubert
Autor Hackl, Hubert Division of Bioinformatics, Biocenter, Medical University Innsbruck, 6020, Innsbruck, Austria
Zeimet, Alain G
Autor Zeimet, Alain G Department of Obstetrics and Gynecology, Medical University Innsbruck, 6020, Innsbruck, Austria

International journal of cancer. 2018 ; 142 (8) : 1640-1651. [pub] 20171214

Int J Cancer
ISSN 1097-0215
Medvik
Zdroj

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.

Článek online

Evaluation of Vav3.1 as prognostic marker in endometrial cancer

Journal of cancer research and clinical oncology. 2018 ; 144 (10) : 2067-2076. [pub] 20180806

J Cancer Res Clin Oncol
ISSN 1432-1335
Medvik
Zdroj

PURPOSE: Vav3 is a guanine nucleotide exchange factor that regulates the activity of Rho/Rac family GTPases. In a study on ovarian cancer, we recently demonstrated pronounced prognostic and predictive value of Vav3.1, a specific truncation variant of the parental Vav3 gene. Here, we sought to investigate the role of Vav3.1 in the most prevalent gynecological tumor entity, endometrial cancer. METHODS: Vav3.1 transcript levels were determined in a large cohort of endometrial cancer patients using variant-specific PCR (n = 239), and non-malignant endometrial tissue served as control (n = 26). Expression levels of Vav3.1 were stratified according to established clinicopathological characteristics and correlated to long-term patient survival (average follow-up of > 7.5 years). Type 1 and type 2 cancers were separately investigated. RESULTS: While Vav3.1 was markedly overexpressed in endometrial cancer tissue, we could not detect associations with clinical parameters related to prognosis, such as FIGO stage and tumor grade. Kaplan-Meier estimators of different measures of survival failed to show prognostic significance of Vav3.1 in endometrial cancer. Lack of prognostic value was observed for both type 1 and type 2 cancers. CONCLUSIONS: Our study shows that Vav3.1 is not suited as a marker of cancer progression and/or treatment response in endometrial cancer. Feasibility and potential benefit of targeting Vav3.1 in endometrial cancer needs to be evaluated in future studies, proceeding from its clear, roughly ten-fold, induction in the malignant endometrium.

MeSH
adenokarcinom z jasných buněk genetika patologie terapie MeSH
dospělí MeSH
kombinovaná terapie MeSH
lidé středního věku MeSH
lidé MeSH
míra přežití MeSH
nádorové biomarkery genetika MeSH
nádory endometria genetika patologie terapie MeSH
následné studie MeSH
prognóza MeSH
protein - isoformy MeSH
protoonkogenní proteiny c-vav genetika MeSH
retrospektivní studie MeSH
senioři nad 80 let MeSH
senioři MeSH
serózní cystadenokarcinom genetika patologie terapie MeSH
studie případů a kontrol MeSH
Check Tag
dospělí MeSH
lidé středního věku MeSH
lidé MeSH
senioři nad 80 let MeSH
senioři MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH

Článek online

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

Nature genetics. 2014 ; 46 (11) : 1187-96.

Nat Genet
ISSN 1546-1718
Medvik
Zdroj

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.