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1.
Oncogene ; 26(50): 7170-4, 2007 Nov 01.
Article in English | MEDLINE | ID: mdl-17525744

ABSTRACT

Cancer stem cells can play an important role in tumorigenesis and tumor progression. However, it is still difficult to detect and isolate cancer stem cells. An alternative approach is to analyse stem cell-associated gene expression. We investigated the coexpression of three stem cell-associated genes, Hiwi, hTERT and survivin, by quantitative real-time-PCR in 104 primary soft-tissue sarcomas (STS). Multivariate Cox's proportional hazards regression analyses allowed correlating gene expression with overall survival for STS patients. Coexpression of all three stem cell-associated genes resulted in a significantly increased risk of tumor-related death. Importantly, tumors of patients with the poorest prognosis were of all four tumor stages, suggesting that their risk is based upon coexpression of stem cell-associated genes rather than on tumor stage.


Subject(s)
Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Sarcoma/genetics , Sarcoma/pathology , Argonaute Proteins , Female , Humans , Inhibitor of Apoptosis Proteins , Male , Microtubule-Associated Proteins/genetics , Neoplasm Proteins/genetics , Prognosis , Proteins/genetics , Sarcoma/etiology , Survivin , Telomerase/genetics
2.
Verh Dtsch Ges Pathol ; 91: 233-42, 2007.
Article in German | MEDLINE | ID: mdl-18314620

ABSTRACT

PURPOSE: Although TP53 is one of the most studied genes/proteins in ovarian carcinomas, the predictive value of TP53 alterations is still ambiguous. EXPERIMENTAL DESIGN: We performed analyses of the TP53 mutational status and its protein expression by immunohistochemistry. Moreover, the single nucleotide polymorphism SNP309 in the P2-promotor of the HDM2 gene was investigated. We correlated the results with the age of onset and the outcome of 107 ovarian carcinoma patients. RESULTS: In our study, we identified a large group of patients with TP53 overexpression despite having a wild-type gene (49% of all patients with wild-type TP53). This was associated with a significantly shortened overall survival time (p = 0.019). Patients with TP53 alterations (especially those with overexpression of wild-type TP53) were also more refractory to chemotherapy than patients with normal TP53 (p = 0.027). The Gallele of the SNP309 is associated with an earlier age of onset in estrogen receptor expressing FIGO stage III patients (p = 0.048). In contrast, in FIGO III patients, a weakened TP53 pathway (either G-allele of SNP309 or a TP53 mutation) is correlated with an increased overall survival compared with patients whose tumors are wild-type for TP53 and SNP309 (p = 0.0035). CONCLUSION: Our study provides evidence that both germ line and somatic alterations of the TP53 pathway influence incidence and survival of ovarian carcinoma, and it underscores the importance of assessing the functionality of TP53 in order to predict sensitivity of platin-based chemotherapies and patient outcome.


Subject(s)
Germ-Line Mutation , Mutation , Ovarian Neoplasms/genetics , Polymorphism, Single Nucleotide , Tumor Suppressor Protein p53/genetics , Base Sequence , Female , Humans , Immunohistochemistry , Incidence , Ovarian Neoplasms/epidemiology , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Prognosis , Survival Analysis
3.
Int J Radiat Biol ; 80(1): 53-63, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14761850

ABSTRACT

PURPOSE: The tumour suppressor protein p53 is considered to have an impact on the radiosensitivity of tumour cells. However, this concept does not easily translate to the tumour sensitivity in the clinics. The aim of the present study was to determine whether a functional or dysfunctional p53 is associated with a sensitive or resistant phenotype. It was further studied whether DNA damage might be an additive factor by which p53 has impact on cell survival. MATERIALS AND METHODS: Nine human tumour cell lines were studied for p53 mutation by direct sequencing of exons 4-9. Regulation of p53 and p21(cip1/waf1) protein was assessed by immunoblotting and cell cycle effects by combining 5-bromodeoxyuridine incorporation and flow cytometry. RESULTS AND CONCLUSION: Three strains (RT112, Du145, SCC4451) were found to have a missense-mutation in the core domain and one did not express p53 at all (HeLa), presumably due to HPV18 infection. Immunoblots of these cells showed neither a regulated p53 nor p21 expression. The cells did not arrest in G1 phase after X-irradiation but did arrest in G2/M. All cells expressing wild-type protein (LNCaP, T47D-B8, MCF-7 and sublines BB and Bus) showed an intact p53 and p21 regulation and a modest arrest in both G1 and G2/M. Thus, in contrast to other studies, all tumour cells investigated showed either a typical p53wt or mutant (mut) pattern. Protein function was compared with cell survival and DNA damage, as assessed previously. p53 wild-type cells were on average 1.3-times (n.s.) more radiosensitive than mutant cells, but there was a considerable overlap between both groups. Further, the 1.3-fold enhanced resistance of cells lacking wild-type p53 was paralleled by a 1.3-fold lower number of induced double-strand breaks. The results suggest that p53 could have impact on chromatin compaction and thus effect DNA damage induction and radiosensitivity of tumour cells.


Subject(s)
DNA Damage , DNA/radiation effects , Neoplasms/enzymology , Neoplasms/genetics , Radiation Tolerance/genetics , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Adaptation, Physiological , Cell Cycle/radiation effects , Cell Line, Tumor/enzymology , Cell Line, Tumor/radiation effects , Cloning, Molecular , Dose-Response Relationship, Radiation , Humans , Mutagenesis, Site-Directed , Neoplasms/pathology , Radiation Dosage , Structure-Activity Relationship , Tumor Suppressor Protein p53/chemistry
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