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1.
Lung Cancer ; 85(2): 282-92, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24976335

RESUMO

BACKGROUND: Large tumor suppressor 2 (LATS2) gene is a putative tumor suppressor gene with potential roles in regulation of cell proliferation and apoptosis in lung cancer. The aim of this study is to explore the association of aberrant LATS2 expression with EGFR mutation and survival in lung adenocarcinoma (AD), and the effects of LATS2 silencing in both lung AD cell lines. METHODS: LATS2 mRNA and protein expression in resected lung AD were correlated with demographic characteristics, EGFR mutation and survival. LATS2-specific siRNA was transfected into four EGFR wild-type (WT) and three EGFR mutant AD cell lines and the changes in LATS2 expression and relevant signaling molecules before and after LATS2 knockdown were assayed. RESULTS: Fifty resected lung AD were included (M:F=23:27, smokers:non-smokers=19:31, EGFR mutant:wild-type=21:29) with LATS2 mRNA levels showed no significant difference between gender, age, smoking and pathological stages while LATS2 immunohistochemical staining on an independent set of 79 lung AD showed similar trend. LATS2 mRNA level was found to be a significant independent predictor for survival status (disease-free survival RR=0.217; p=0.003; Overall survival RR=0.238; p=0.036). siRNA-mediated suppression of LATS2 expression resulted in augmentation of ERK phosphorylation in EGFR wild-type AD cell lines with high basal LATS2 expression, discriminatory modulation of Akt signaling between EGFR wild-type and mutant cells, and induction of p53 accumulation in AD cell lines with low baseline p53 levels. CONCLUSIONS: LATS2 expression level is predictive of survival in patients with resected lung AD. LATS2 may modulate and contribute to tumor growth via different signaling pathways in EGFR mutant and wild-type tumors.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Receptores ErbB/genética , Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Análise Mutacional de DNA , Receptores ErbB/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Inativação Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Sistema de Sinalização das MAP Quinases , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo
3.
Asian Cardiovasc Thorac Ann ; 18(1): 33-8, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20124294

RESUMO

A potential limitation of integrated positron-emission tomography and computed tomography in non-small-cell lung cancer may be false-positive results due to granulomatous disease. This retrospective study examined the accuracy of this imaging modality for mediastinal nodal staging of non-small-cell lung cancer in Hong Kong where tuberculosis remains endemic. There were 249 lymph node stations evaluated in 107 patients, of whom 38 (36%) had active tuberculosis or evidence of previous tuberculosis. Imaging results were compared with histological findings. The sensitivity, specificity, and accuracy of integrated imaging for mediastinal nodal staging were 52%, 86%, and 80%, respectively; the overall positive-predictive value for mediastinal nodal metastasis was 46%, and the overall negative-predictive value was 89%. The positive-predictive value for mediastinal nodal metastasis was 39% in patients with tuberculosis and 50% in controls; the negative-predictive value was high in both groups (92% and 87%). The likelihood ratio for true positives was 6.47 in patients with tuberculosis vs. 10.97 in controls. This suggests that the reliability of positron-emission/computed tomography may be substantially poorer in patients with tuberculosis. Histological confirmation should be considered mandatory in patients with suspected metastasis on integrated imaging.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Doenças Endêmicas/estatística & dados numéricos , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tuberculose/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos de Coortes , Comorbidade , Feminino , Hong Kong/epidemiologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/cirurgia , Metástase Linfática , Masculino , Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
4.
Cancer Res ; 67(10): 4638-47, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17510389

RESUMO

Nicotine and its derivatives, by binding to nicotinic acetylcholine receptors (nAChR) on bronchial epithelial cells, can regulate cellular proliferation and apoptosis via activating the Akt pathway. Delineation of nAChR subtypes in non-small-cell lung cancers (NSCLC) may provide information for prevention or therapeutic targeting. Expression of nAChR subunit genes in 66 resected primary NSCLCs, 7 histologically non-involved lung tissues, 13 NSCLC cell lines, and 6 human bronchial epithelial cell lines (HBEC) was analyzed with quantitative PCR and microarray analysis. Five nonmalignant HBECs were exposed to nicotine in vitro to study the variation of nAChR subunit gene expression with nicotine exposure and removal. NSCLCs from nonsmokers showed higher expression of nAChR alpha6 (P < 0.001) and beta3 (P = 0.007) subunit genes than those from smokers, adjusted for gender. In addition, nAChR alpha4 (P < 0.001) and beta4 (P = 0.029) subunit gene expression showed significant difference between NSCLCs and normal lung. Using Affymetrix GeneChip U133 Sets, 65 differentially expressed genes associated with NSCLC nonsmoking nAChR alpha6beta3 phenotype were identified, which gave high sensitivity and specificity of prediction. nAChR alpha1, alpha5, and alpha7 showed significant reversible changes in expression levels in HBECs upon nicotine exposure. We conclude that between NSCLCs from smokers and nonsmokers, different nAChR subunit gene expression patterns were found, and a 65-gene expression signature was associated with nonsmoking nAChR alpha6beta3 expression. Finally, nicotine exposure in HBECs resulted in reversible differences in nAChR subunit gene expression. These results further implicate nicotine in bronchial carcinogenesis and suggest targeting nAChRs for prevention and therapy in lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Receptores Nicotínicos/genética , Fumar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Brônquios/citologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Feminino , Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Nicotina/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Nicotínicos/biossíntese , Fumar/efeitos adversos , Fumar/metabolismo
5.
Cancer Lett ; 245(1-2): 303-14, 2007 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-16517066

RESUMO

Tumours develop from clonally expanded population of cells harbouring aberrations of oncogenes and tumour suppressor genes. In this study, metaphase and array comparative genomic hybridization showed good correlation of aberration profiles in lung adenocarcinoma cell lines from patients with different tobacco exposure. Recurrent DNA gains were found at chromosomes 1, 7, 8, 17, 20, and deletions at 1, 3, 8, 9, 10, 12, 17, 18, 19. Candidate tumour loci and encompassed genes at 7p21 (AGR2), 8q21(TPD52), 20q13 (ZNF217, WFDC2, EEF1A2) and 10p15 (KLF6) were analyzed by dual colour FISH for genomic changes and quantitative PCR for expression changes. Results indicated that EEF1A2 and KLF6 were strong candidates of oncogene and tumour suppressor genes, respectively. This study illustrates, a practical strategy for identifying candidate cancer genes from microarray data.


Assuntos
Adenocarcinoma/genética , Aberrações Cromossômicas , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Hibridização de Ácido Nucleico/métodos , Adenocarcinoma/patologia , Idoso , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/patologia , Masculino , Metáfase/genética , Análise em Microsséries/métodos , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
6.
Clin Cancer Res ; 12(5): 1647-53, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16533793

RESUMO

PURPOSE: This study evaluated the mutational profile of epidermal growth factor receptor (EGFR) and KRAS in non-small cell lung cancers in Hong Kong and determined their relation with smoking history and other clinicopathologic features. EXPERIMENTAL DESIGN: Mutational profile of exons 18 to 21 of EGFR and codons 12, 13, and 61 of KRAS were determined in 215 adenocarcinomas, 15 squamous cell (SCC), and 11 EBV-associated lymphoepithelioma-like carcinomas (LELC). RESULTS: EGFR mutations were prevalent in adenocarcinomas (115 of 215), uncommon in LELC (1 of 11), and not found in SCC (P < 0.001). Among adenocarcinomas, mutations were associated with nonsmokers (83 of 111; P < 0.001), female gender (87 of 131; P < 0.001), and well-differentiated (55 of 86) compared with poorly differentiated (11 of 41) tumors (P < 0.001). Decreasing mutation rates with increasing direct tobacco exposure was observed, with 74.8% (83 of 111) in nonsmokers, 61.1% (11 of 18) in passive, 35.7% (10 of 28) in previous, and 19.0% (11 of 58) in current smokers. There were 53% amino acid substitutions, 43% in-frame deletions, and 4% insertions. Complex patterns with 13% double mutations, including five novel substitutions, were observed. For KRAS, mutations occurred in adenocarcinoma only (21 of 215) and were associated with smokers (11 of 58; P = 0.003), men (14 of 84; P = 0.009) and poorly differentiated (7 of 41) compared with well-differentiated (4 of 86) tumors (P = 0.037). EGFR and KRAS mutations occurred in mutually exclusive tumors. Regression analysis showed smoking history was the significant determinant for both mutations, whereas gender was a confounding factor. CONCLUSION: This study shows EGFR mutations are prevalent in lung adenocarcinoma and suggests that it plays an increasing oncogenic role with decreasing direct tobacco damage.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Genes ras/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Diferenciação Celular , Análise Mutacional de DNA , Éxons , Feminino , Regulação Neoplásica da Expressão Gênica , Infecções por Herpesviridae/complicações , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/patologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Hong Kong , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Nódulo Pulmonar Solitário/diagnóstico , Nódulo Pulmonar Solitário/genética , Nódulo Pulmonar Solitário/virologia , Poluição por Fumaça de Tabaco
7.
J Thorac Oncol ; 1(9): 932-42, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17409975

RESUMO

BACKGROUND: Bronchogenic adenocarcinoma is the predominant histologic subtype of lung cancer, which ranks top in the cancer mortality in both men and women. Female nonsmokers and adenocarcinoma have emerged as a distinct combination in patients with lung cancer in recent decades. Lung cancer cell lines established from patients with known clinical characteristics such as gender and smoking habit would be useful for future research on lung cancer. METHODS: Four new lung adenocarcinoma cell lines (HKULC 1-4) were established from Chinese patients with primary lung adenocarcinomas and with different clinical characteristics with respect to age, gender, smoking habits, tumor staging, and previous therapy. They were characterized by immunohistochemical and growth kinetic studies, tests for tumorigenicity in nude mice, epidermal growth factor receptor (EGFR) gene mutation analysis, and in situ hybridization, and gene expression profiling with Affymetrix GeneChip HG-U133A. RESULTS: The newly established HKULC lung adenocarcinoma cell lines were maintained for over 70 passages and demonstrated morphologic and immunohistochemical features and growth kinetics of tumor cell lines. One of the four HKULC cell lines, HKULC 3 (derived from a female nonsmoking patient with lung adenocarcinoma), was found to have a deletion at exon 19 of the EGFR gene. EGFR in situ hybridization showed no EGFR gene amplification in these cell lines. HKULC 1 and 4 formed tumor xenografts after inoculation in nude mice. A list of 71 genes that were differentially expressed or showing class predictive significance was identified. These genes included putative tumor suppressor genes (DKK3, SERPINF1, CDH11, DSC3, and KLF6), genes involved in or related to the EGFR pathways (ERBB3, MUC1, VAV1), genes involved in regulation of cell cycle and proliferation (CDKN1A and CDKN2A), a putative oncogene (EEF1A2), and a gene related to metastasis (MTSS1). DISCUSSION: Four new lung adenocarcinoma cell lines were established from patients with different clinical characteristics. These characterized cell lines and their gene expression profiles will provide resources for studies of lung cancer biology and in vitro chemotherapeutic drug study.


Assuntos
Receptores ErbB/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Adenocarcinoma/etnologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Animais , Linhagem Celular Tumoral , China , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização In Situ , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Valores de Referência , Sensibilidade e Especificidade
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