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1.
Ann Oncol ; 23(7): 1795-802, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22228447

RESUMO

BACKGROUND: Overexpression of L1-cell adhesion molecule (L1CAM) has been observed for various carcinomas and correlates with poor prognosis and late-stage disease. In vitro, L1CAM enhances proliferation, cell migration, adhesion and chemoresistance. We tested L1CAM and interleukin-1 beta (IL-1ß) expression in tumor samples and ascitic fluid from ovarian carcinoma patients to examine its role as a prognostic marker. PATIENTS AND METHODS: We investigated tumor samples and ascitic fluid from 232 serous ovarian carcinoma patients for L1CAM by enzyme-linked immunosorbent assay. L1CAM expression was correlated with pathoclinical parameters and patients' outcome. IL-1ß levels were measured in tumor cell lysates. Ovarian cancer cell lines were analyzed for the contribution of L1CAM to IL-1ß production and nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB) activation. RESULTS: We observed that L1CAM-expressing tumors show a highly invasive phenotype associated with restricted tumor resectability at primary debulking surgery and increased lymphogenic spread. Soluble L1CAM proved to be a marker for poor progression-free survival and chemoresistance. In ovarian carcinoma cell lines, the specific knock-down of L1CAM reduces IL-1ß expression and NF-κB activity. CONCLUSIONS: L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1ß production and NF-κB activation.


Assuntos
Carcinoma/metabolismo , NF-kappa B/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Ovarianas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Ascítico/metabolismo , Carcinoma/mortalidade , Carcinoma/secundário , Carcinoma/terapia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Estimativa de Kaplan-Meier , Metástase Linfática , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Fenótipo , Prognóstico , Adulto Jovem
2.
Oncogene ; 30(38): 4038-49, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21516127

RESUMO

Recently we showed an integral epidermal growth factor receptor (EGFR)-E2F3a signaling path, in which E2F3a was found to be essential in EGFR-mediated proliferation in ovarian cancer cells. The present work evaluates the clinical relevance of this novel axis and of E2F3a itself in a large set of 130 ovarian cancer specimens. For this purpose E2F3a and its counterpart, E2F3b, were measured by RT-PCR and activated EGFR was assessed by immunohistochemistry. When compared with healthy control tissue, both E2F3 isoforms were overexpressed in the cancers, but only E2F3a expression correlated with tumor stage (ρ=0.349, P=0.0001) and residual disease (ρ=0.254, P=0.004). Univariate survival analyses showed E2F3a and activated EGFR to be associated with poor PFS and OS. Furthermore, a strong, positive correlation between activated EGFR and E2F3a expression was shown (P=0.0001). We further identified two EGFR-independent mechanisms that regulate E2F3a expression, namely one, acting by promoter methylation of miR-34a, which by its physical interaction with E2F3a transcripts causes their degradation, and the second based on 6p22 gene locus amplification. MiRIDIAN-based knockdown and induction of miR-34a evidenced a direct regulatory link between miR-34a and E2F3a, and the tumor-suppressive character of miR-34a was documented by its association with improved survival. Although, 6p22 gene locus amplification was detected in a significant number of ovarian cancer specimens, 6p22 ploidy was not relevant in predicting survival. In Cox regression analysis, E2F3a, but not activated EGFR or miR-34a expression, retained independent prognostic significance (PFS: hazards ratio 3.785 (1.326-9.840), P=0.013; OS: hazards ratio 4.651 (1.189-15.572), P=0.013). These clinical findings highlight the relevance of E2F3a in the biology of ovarian cancer. Moreover, identification of EGFR-independent mechanisms in E2F3a control can be helpful in explaining the non-responsiveness of therapeutic EGFR targeting in ovarian cancer.


Assuntos
Fator de Transcrição E2F3/fisiologia , Neoplasias Ovarianas/patologia , Idoso , Cromossomos Humanos Par 6 , Metilação de DNA , Fator de Transcrição E2F3/análise , Fator de Transcrição E2F3/genética , Receptores ErbB/fisiologia , Feminino , Amplificação de Genes , Humanos , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Ovarianas/química , Neoplasias Ovarianas/genética , Prognóstico , Regiões Promotoras Genéticas
3.
Oncogene ; 29(34): 4766-78, 2010 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-20543863

RESUMO

L1 cell adhesion molecule (L1CAM) overexpression is often associated with bad prognosis in various human carcinomas. Recent studies also suggest a role of L1CAM in pancreatic ductal adenocarcinomas (PDAC). To further address its contribution, we expressed functional domains of L1CAM in PT45-P1 PDAC cells. We found that L1CAM that is full length (L1-FL), but neither the soluble ectodomain (L1ecto) nor the cytoplasmic part (L1cyt), could enhance cell proliferation or tumour growth in mice. Expression of L1-FL resulted in constitutive activation of NF-kappaB, which was abolished by L1CAM knockdown. We showed that the expression of IL-1beta was selectively upregulated by L1-FL, and increased IL-1beta levels were instrumental for sustained NF-kappaB activation. IL-1beta production and NF-kappaB activation were abolished by knockdown of alpha5-integrin and integrin-linked kinase, but insensitive to depletion of L1CAM cleavage proteinases. Supporting these data, PT45-P1 cells transduced with an L1CAM mutant deficient in integrin binding (L1-RGE) did not support the described L1-FL functions. Our results suggest that membranous L1CAM interacts with RGD-binding integrins, leading to sustained NF-kappaB activation by IL-1beta production and autocrine/paracrine signalling. The unravelling of this novel mechanism sheds new light on the important role of L1CAM expression in PDAC cells.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Interleucina-1beta/biossíntese , NF-kappa B/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Adesão Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NF-kappa B/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Acetato de Tetradecanoilforbol/farmacologia , Transfecção
4.
Hum Reprod ; 23(5): 1053-62, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18332088

RESUMO

BACKGROUND: Endometriosis is a benign and progressive disease with a high prevalence. Women with endometriosis, especially with atypical endometriosis, have a higher probability for developing ovarian cancer compared with women without endometriosis. The L1 cell adhesion molecule (L1CAM) is over expressed in ovarian and endometrial carcinomas and is associated with a bad prognosis. Here, we have analysed L1CAM expression in endometriosis. METHODS AND RESULTS: In our study with the samples from 79 patients with, and 37 patients without, endometriosis, we found that endometriosis cell lines and short-term cultures of endometrium from women with endometriosis expressed L1CAM at the mRNA and protein level. Quantitative RT-PCR analysis showed that L1CAM was expressed at significantly higher level in the epithelial compartment from patients with endometriosis compared with healthy controls (P = 0.0126). By immunohistochemical staining, 15 of 31 ovarian endometriotic lesions (48%) were shown to have L1CAM-positive staining. Of these 15 L1CAM-positive samples, 13 were atypical endometriotic lesions. Soluble L1 present in the conditioned medium of epithelial endometrium cultures from women with endometriosis was able to stimulate neurite outgrowth as measured in a chicken ganglion assay. CONCLUSIONS: We propose that L1CAM could promote endometriosis development by increasing enervation and aggravation. L1CAM expression is higher in atypical endometriosis compared with normal endometriosis.


Assuntos
Endometriose/fisiopatologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Proteínas ADAM/biossíntese , Proteína ADAM10 , Adulto , Secretases da Proteína Precursora do Amiloide/biossíntese , Animais , Células Cultivadas , Embrião de Galinha , Meios de Cultura/farmacologia , Feminino , Humanos , Imuno-Histoquímica , Proteínas de Membrana/biossíntese , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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