Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Cancer Lett ; 383(1): 106-114, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693639

RESUMO

Oral squamous cell carcinoma (OSCC) is genetically highly heterogeneous, which contributes to the challenges of treatment. To create an in vitro model that accurately reflects this heterogeneity, we generated a panel of HPV-negative OSCC cell lines. By whole exome sequencing of the lines and matched patient blood samples, we demonstrate that the mutational spectrum of the lines is representative of primary OSCC in The Cancer Genome Atlas. We show that loss of function mutations in FAT1 (an atypical cadherin) and CASP8 (Caspase 8) frequently occur in the same tumour. OSCC cells with inactivating FAT1 mutations exhibited reduced intercellular adhesion. Knockdown of FAT1 and CASP8 individually or in combination in OSCC cells led to increased cell migration and clonal growth, resistance to Staurosporine-induced apoptosis and, in some cases, increased terminal differentiation. The OSCC lines thus represent a valuable resource for elucidating the impact of different mutations on tumour behaviour.


Assuntos
Caderinas/metabolismo , Carcinoma de Células Escamosas/enzimologia , Caspase 8/metabolismo , Genômica , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias Bucais/enzimologia , Antineoplásicos/farmacologia , Apoptose , Caderinas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Caspase 8/genética , Adesão Celular , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Mutação , Invasividade Neoplásica , Fenótipo , Interferência de RNA , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Estaurosporina/farmacologia , Transfecção
3.
Cell Rep ; 9(1): 104-117, 2014 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-25284788

RESUMO

Metastatic colonization of distant organs underpins the majority of human-cancer-related deaths, including deaths from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that triggers differentiation in multilayered epithelia, inhibits multiple postextravasation events during HNSCC lung metastasis. Inducible reactivation of miR-203 in already established lung metastases reduces the overall metastatic burden. Using an integrated approach, we reveal that miR-203 inhibits metastasis independently of its effects on differentiation. In vivo genetic reconstitution experiments show that miR-203 inhibits lung metastasis by suppressing the prometastatic activities of three factors involved in cytoskeletal dynamics (LASP1), extracellular matrix remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream effectors correlates with HNSCC overall survival outcomes, indicating the therapeutic potential of targeting this signaling axis.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Animais , Carcinoma de Células Escamosas/metabolismo , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proteínas do Citoesqueleto/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/metabolismo , Xenoenxertos , Humanos , Proteínas com Domínio LIM/antagonistas & inibidores , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Metástase Neoplásica , Osteonectina/antagonistas & inibidores , Prognóstico , Proteínas Quinases , Proteínas Repressoras/antagonistas & inibidores , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço
4.
Int J Biol Sci ; 10(7): 702-14, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25013379

RESUMO

A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Carcinoma de Células Escamosas/tratamento farmacológico , Proliferação de Células , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Proteínas ADAM/genética , Proteínas ADAM/imunologia , Proteínas ADAM/metabolismo , Proteínas ADAM/fisiologia , Proteína ADAM10 , Proteína ADAM17 , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Secretases da Proteína Precursora do Amiloide/fisiologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Gefitinibe , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia , Fosforilação , Quinazolinas/farmacologia , Transdução de Sinais
5.
J Peripher Nerv Syst ; 17(1): 76-89, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22462669

RESUMO

Peripheral neuropathy is a common side effect of a number of pharmaceutical compounds, including several chemotherapy drugs. Among these are vincristine sulfate, a mitotic inhibitor used to treat a variety of leukemias, lymphomas, and other cancers, and bortezomib, a 26S proteasome inhibitor used primarily to treat relapsed multiple myeloma and mantle cell lymphoma. To gain insight into the mechanisms by which these compounds act, we tested their effects in zebrafish. Vincristine or bortezomib given during late embryonic development caused significant defects at both behavioral and cellular levels. Intriguingly, the effects of the two drugs appear to be distinct. Vincristine causes uncoordinated swimming behavior, which is coupled with a reduction in the density of sensory innervation and overall size of motor axon arbors. Bortezomib, in contrast, increases the duration and amplitude of muscle contractions associated with escape swimming, which is coupled with a preferential reduction in fine processes and branches of sensory and motor axons. These results demonstrate that zebrafish is a convenient in vivo assay system for screening potential pharmaceutical compounds for neurotoxic side effects, and they provide an important step toward understanding how vincristine and bortezomib cause peripheral neuropathy.


Assuntos
Antineoplásicos/efeitos adversos , Axônios/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Ácidos Borônicos/efeitos adversos , Pirazinas/efeitos adversos , Vincristina/efeitos adversos , Animais , Axônios/patologia , Bortezomib , Imuno-Histoquímica , Larva/efeitos dos fármacos , Peixe-Zebra
6.
Genes Dev ; 25(6): 646-59, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21406558

RESUMO

Distant metastases, rather than the primary tumors from which these lesions arise, are responsible for >90% of carcinoma-associated mortality. Many patients already harbor disseminated tumor cells in their bloodstream, bone marrow, and distant organs when they initially present with cancer. Hence, truly effective anti-metastatic therapeutics must impair the proliferation and survival of already-established metastases. Here, we assess the therapeutic potential of acutely expressing the microRNA miR-31 in already-formed breast cancer metastases. Activation of miR-31 in established metastases elicits metastatic regression and prolongs survival. Remarkably, even brief induction of miR-31 in macroscopic pulmonary metastases diminishes metastatic burden. In contrast, acute miR-31 expression fails to affect primary mammary tumor growth. miR-31 triggers metastatic regression in the lungs by eliciting cell cycle arrest and apoptosis; these responses occur specifically in metastases and can be explained by miR-31-mediated suppression of integrin-α5, radixin, and RhoA. Indeed, concomitant re-expression of these three proteins renders already-seeded pulmonary metastases refractory to miR-31-conferred regression. Upon miR-31 activation, Akt-dependent signaling is attenuated and the proapoptotic molecule Bim is induced; these effects occur in a metastasis-specific manner in pulmonary lesions and are abrogated by concurrent re-expression of integrin-α5, radixin, and RhoA. Collectively, these findings raise the possibility that intervention strategies centered on restoring miR-31 function may prove clinically useful for combating metastatic disease.


Assuntos
Neoplasias da Mama/fisiopatologia , MicroRNAs/metabolismo , Metástase Neoplásica/fisiopatologia , Animais , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Ciclo Celular/fisiologia , Linhagem Celular , Proteínas do Citoesqueleto/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Neoplasias Pulmonares/secundário , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica/terapia , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas , Proteína rhoA de Ligação ao GTP/metabolismo
7.
Cancer Res ; 70(12): 5147-54, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20530680

RESUMO

miR-31 inhibits breast cancer metastasis via the pleiotropic suppression of a cohort of prometastatic target genes that include integrin alpha(5) (ITGA5), radixin (RDX), and RhoA. We previously showed that the concomitant overexpression of ITGA5, RDX, and RhoA was capable of overriding the antimetastatic effects of ectopically expressed miR-31 in vivo. However, these prior studies failed to investigate whether the combined suppression of the endogenous mRNAs encoding these three proteins recapitulated the in vivo consequences of miR-31 expression on metastasis. We show here that short hairpin RNA-mediated concurrent downregulation of ITGA5, RDX, and RhoA is sufficient to phenocopy the full spectrum of described influences of miR-31 on metastasis in vivo, including the effects of this microRNA (miRNA) on local invasion, early post-intravasation events, and metastatic colonization. These findings provide mechanistic insights into the metastatic process and have implications about the importance of pleiotropy for the biological actions of miRNAs.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas do Citoesqueleto/metabolismo , Integrina alfa5/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , MicroRNAs/fisiologia , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Adesão Celular , Movimento Celular , Proliferação de Células , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Integrina alfa5/química , Integrina alfa5/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/genética
8.
Genes Dev ; 23(22): 2592-7, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19875476

RESUMO

It remains unclear whether a microRNA (miRNA) affects a given phenotype via concomitant down-regulation of its entire repertoire of targets or instead by suppression of only a modest subset of effectors. We demonstrate that inhibition of breast cancer metastasis by miR-31-a miRNA predicted to modulate >200 mRNAs-can be entirely explained by miR-31's pleiotropic regulation of three targets. Thus, concurrent re-expression of integrin-alpha5, radixin, and RhoA abrogates miR-31-imposed metastasis suppression. These effectors influence distinct steps of the metastatic process. Our findings have implications concerning the importance of pleiotropy for the biological actions of miRNAs and provide mechanistic insights into metastasis.


Assuntos
Neoplasias da Mama/fisiopatologia , Carcinoma Ductal de Mama/fisiopatologia , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , MicroRNAs/metabolismo , Metástase Neoplásica/fisiopatologia , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos
9.
Cell ; 137(6): 1032-46, 2009 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-19524507

RESUMO

MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Metástase Neoplásica , Animais , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/genética , Receptores Frizzled/genética , Humanos , Integrina alfa5/genética , Proteínas de Membrana/genética , Receptores Acoplados a Proteínas G/genética , Proteína rhoA de Ligação ao GTP/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...