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1.
Cancer Cell ; 22(3): 404-15, 2012 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-22975381

RESUMO

Twist proteins have been shown to contribute to cancer development and progression by impinging on different regulatory pathways, but their mechanism of action is poorly defined. By investigating the role of Twist in sarcomas, we found that Twist1 acts as a mechanism alternative to TP53 mutation and MDM2 overexpression to inactivate p53 in mesenchymal tumors. We provide evidence that Twist1 binds p53 C terminus through the Twist box. This interaction hinders key posttranslational modifications of p53 and facilitates its MDM2-mediated degradation. Our study suggests the existence of a Twist box code of p53 inactivation and provides the proof of principle that targeting the Twist box:p53 interaction might offer additional avenues for cancer treatment.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Sarcoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Animais , Transformação Celular Neoplásica , Variações do Número de Cópias de DNA , Transição Epitelial-Mesenquimal , Humanos , Camundongos , Camundongos Nus , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Fosforilação , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Interferência de RNA , RNA Interferente Pequeno , Proteínas Repressoras/metabolismo , Proteína 1 Relacionada a Twist/biossíntese , Proteína 1 Relacionada a Twist/genética
2.
Oncotarget ; 2(12): 1165-75, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22201613

RESUMO

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumors with variable presentation and clinical behavior. Despite improvements in surgical and radiation therapy techniques, the 5-year survival rate has not improved significantly over the past decades. Thus, there is an urgent need to identify novel markers that may allow for the development of personalized therapeutic approaches. In the present study we evaluated the prognostic role of the expression of genes related to the induction of epithelial mesenchymal transition (EMT). To this aim, a consecutive series of 69 HNSCC were analyzed for the expression of TWIST1, TWIST2, SNAI1, SNAI2, E-Cadherin, N-Cadherin and Vimentin.TWIST1, TWIST2, SNAI1 and SNAI2 were significantly overexpressed in HNSCC, with TWIST2, SNAI1 and SNAI2 being more markedly increased in tumors compared to normal mucosae. The expression of TWIST1 and SNAI2 was associated with upregulation of mesenchymal markers, but failed to correlate with pathological parameters or clinical behaviour. In contrast, we found that upregulation of TWIST2, which was independent of the activation of a mesenchymal differentiation program, correlated with poor differentiation grade (p=0.016) and shorter survival (p=0.025), and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (p less than 0.001). Overall our study suggests that the assessment of TWIST2 expression might help to stratify HNSCC patients for risk of disease progression, pointing to TWIST2 as a potential prognostic marker.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Proteínas Repressoras/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Biomarcadores Tumorais , Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Prognóstico , Fatores de Transcrição da Família Snail , Carcinoma de Células Escamosas de Cabeça e Pescoço , Fatores de Transcrição/metabolismo , Vimentina/metabolismo
3.
Clin Cancer Res ; 14(18): 5715-21, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18779314

RESUMO

PURPOSE: Gastrointestinal stromal tumors (GIST) are commonly regarded as solitary tumors. The occurrence of multiple lesions is considered an extraordinary event restricted to pediatric GISTs and rare hereditary conditions. Beyond these well-defined situations, the presentation of multiple synchronous lesions is commonly viewed as the result of the metastatic spreading of a single primary GIST. Based on this axiom, patients with multifocal disease are classified as advanced stage and treated as such. Whether, indeed, the detection of several lesions in sporadic adult GIST patients may be suggestive of phenomena of tumor multiplicity still needs to be clarified. EXPERIMENTAL DESIGN: From a multicentric series of 442 consecutive cases, 26 of which with advanced disease, we selected 5 patients who presented up to three distinct GIST nodules. Five additional cases with similar characteristics were also contributed by two other institutions. The clonal relationship between the synchronous lesions was assessed by comparing KIT/PDGFRA mutation and microsatellite pattern. RESULTS: An independent origin of the synchronous lesions was established in 6 of 10 cases. Notably, in one patient, one lesion arose in the peritoneum, which is ordinarily regarded as a site of metastasis. CONCLUSIONS: Our data indicate that a significant fraction of GIST patients with multifocal presentation are actually affected by multiple primary tumors, suggesting that mesenchymal GIST precursor cells of these individuals are somehow primed to transformation. Thus, in the presence of multifocal GIST manifestations, an accurate characterization of the different tumor sites should be undertaken for a proper patient staging and therapy planning.


Assuntos
Tumores do Estroma Gastrointestinal/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/genética
4.
Int J Cancer ; 123(6): 1466-71, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18566993

RESUMO

CDC25A phosphatase, an essential component of the cell cycle machinery, is also a key player in integrating the specific signals of checkpoint control in response to DNA damage. There are several lines of evidence that indicate a role for CDC25A in cancer development, consistent with the fact that its overexpression is detected in human cancers. In particular we previously reported that CDC25A is overexpressed also in early breast carcinoma. Recent data suggest that oncogene activation during early stages of tumor development causes DNA replication stress resulting in the induction of DNA damage response (DDR) and that the selection of cells defecting in their DDR could lead to malignant progression. To address how CDC25A overexpression contributes to breast cancer development we established a cell model in which CDC25A was constitutively overexpressed in hTERT-immortalized primary human mammary epithelial cells. At the earliest passages following CDC25A transduction we observed DDR signs associated with unscheduled DNA replication origins. In the latest passages DDR was significantly impaired and, even after ionizing radiation exposition, cells failed to induce G1 and G2 checkpoints; moreover DNA replication stress conditions, such as aphidicolin treatment, highlighted increased fragile site breakages and destabilized chromosomes just in these latest passages cells. Our data suggest that CDC25A overexpression, pushing the cell through the cell cycle transitions, induces DDR alterations that might enhance genomic instability.


Assuntos
Neoplasias da Mama/genética , Transformação Celular Neoplásica/genética , Reparo do DNA , Células Epiteliais/metabolismo , Glândulas Mamárias Humanas/metabolismo , Fosfatases cdc25/biossíntese , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Dano ao DNA , Células Epiteliais/patologia , Feminino , Imunofluorescência , Humanos , Hibridização in Situ Fluorescente , Glândulas Mamárias Humanas/patologia , Regulação para Cima
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