RESUMO
BHLHB3 is a basic helix-loop-helix (bHLH) domain-containing protein that acts as a transcriptional repressor. We found that BHLHB3 transcript levels were low in three human lung cancer cell lines and downregulated in human lung adenocarcinomas as compared to normal lung tissue. BHLHB3 gene overexpression inhibited colony formation of A549, NCI-H520 and NCI-H596 lung cancer cells. The reduced colony growth was likely due to inhibition of cell proliferation as suggested by the downregulation of cyclin D1 (CCND1) expression in NCI-H520 cells transfected to overexpress the BHLHB3 gene; no evidence of apoptosis was observed. These results point to the potential role of the BHLHB3 protein as a tumor suppressor for lung cancer.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Neoplasias Pulmonares/prevenção & controle , Proteínas Supressoras de Tumor/fisiologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Ciclina D1/genética , Humanos , Regiões Promotoras Genéticas , RNA Mensageiro/análiseRESUMO
Evidence in animal models has suggested an association between susceptibility to lung tumorigenesis and gene-expression profiles in normal lung. Here, we compared RNA pools from normal lung tissue of lung adenocarcinoma patients (cases) or non-lung cancer patients (controls) by hybridization of whole-human genome expression arrays. Principal component analysis identified a gene-expression signature of 85 genes that distinguishes cases from controls as well as smokers from nonsmokers. Elevated mRNA levels of one of these genes, AZGP1, were significantly associated with disease status. These results support the hypothesis that differences in the gene-expression levels of the normal tissue may be predictive of genetic predisposition to lung cancer in humans.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/genética , Glicoproteínas/genética , Pulmão/metabolismo , RNA Mensageiro/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adipocinas , Idoso , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de TecidosRESUMO
Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.
Assuntos
Glutationa Transferase/genética , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Povo Asiático/estatística & dados numéricos , Estudos de Casos e Controles , Interpretação Estatística de Dados , Predisposição Genética para Doença , Variação Genética , Genótipo , Glutationa Transferase/fisiologia , Humanos , Neoplasias Pulmonares/etnologia , Polimorfismo Genético , Fatores de Risco , Fumar/efeitos adversos , População Branca/estatística & dados numéricosRESUMO
The RASSF8 gene, which maps close to the KRAS2 gene, contains a RAS-associated domain and encodes a protein that is evolutionarily conserved from fish to humans. Analysis of the RASSF8 transcript revealed a complex expression pattern of 5'-UTR mRNA isoforms in normal lung and in lung adenocarcinomas (ADCAs), with no apparent differences. However, RASSF8 gene transcript levels were approximately seven-fold-lower in lung ADCAs as compared to normal lung tissue. Expression of RASSF8 protein by transfected lung cancer cells led to inhibition of anchorage-independent growth in soft agar in A549 cells and reduction of clonogenic activity in NCI-H520 cells. These results raise the possibility protein encoded by RASSF8 is a novel tumor suppressor for lung cancer.
Assuntos
Adenocarcinoma/genética , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas , Adenocarcinoma/patologia , Sequência de Bases , Adesão Celular/genética , Divisão Celular/genética , Linhagem Celular Tumoral , Clonagem Molecular , Primers do DNA , Regulação para Baixo , Humanos , Neoplasias Pulmonares/patologia , Dados de Sequência Molecular , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
The non-coding variation in the second intron of the L-myc gene, generating an EcoRI polymorphism, is associated with lung cancer risk and prognosis. We carried out sequence analysis of the L-myc gene in lung adenocarcinoma (ADCA) patients to identify functional polymorphisms and identified a new single nucleotide polymorphism (SNP) in the third exon of the gene causing a Ser362Thr conservative amino acid change in the C-terminus of the encoded protein. This polymorphism showed significant linkage disequilibrium with the L-myc EcoRI polymorphism located at 1751 bp distance. Genotyping of the Ser362Thr SNP in 220 Italian ADCA patients and in 230 general population controls revealed a similar low frequency (0.10-0.11) of the Thr allele in both groups. The multivariate odds ratio was 0.68 (95% confidence interval (CI) 0.38-1.22). In the ADCA patients, no significant association between the Ser/Thr polymorphism and survival was observed. Thus, the present results do not support candidacy of the L-myc Ser362Thr polymorphism for the functional polymorphism of the L-myc genomic region.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Genes myc/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
Italian and Japanese non-small-cell lung-cancer patients were genotyped for an intragenic L-myc EcoRI restriction site polymorphism previously reported to be associated with lung-tumor prognosis in Asian populations but not in Caucasians. Screening of the L-myc sequence in Italian samples allowed identification of 2 additional 3'-UTR SNPs, located 2.3-3.0 kb from the EcoRI polymorphism, but no coding polymorphism was found. No significant association was found between any of the 3 SNPs and lung-tumor prognosis in Italian patients, consistent with the reported difference between Caucasian and Asian populations. Moreover, the newly discovered polymorphisms in the Italian group were not present in Japanese patients. Significant LD between EcoRI and the 2 other SNPs was detected in the Italian population, whereas no significant LD between the 2 3'-UTR markers was detected despite their close proximity (0.7 kb). Thus, the disparate conclusions about the role of L-myc polymorphism in tumor prognosis among different populations may rest in population-specific LD between the functional gene and the L-myc polymorphism.
Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Genes myc/genética , Desequilíbrio de Ligação , Neoplasias Pulmonares/genética , Adenocarcinoma/patologia , Alelos , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Marcadores Genéticos/genética , Humanos , Itália , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Prognóstico , Análise de Sequência de DNARESUMO
Nasal provocation tests with lysine acetylsalicylic acid (ASA) have been used in the diagnosis of ASA-induced asthma and rhinitis. To establish its possible role in identifying aspirin sensitivity manifested by urticaria or angioedema, 18 patients suffering from chronic or acute recurring urticaria/angioedema (10 ASA-sensitive and 8 ASA-nonsensitive) were submitted to nasal provocation tests with freshly prepared solutions of lysine ASA. Clinical response and variation of nasal expiratory peak-flow were evaluated, classified according to previously defined scores, and compared. The results showed a significant difference between ASA-sensitive and ASA-nonsensitive patients, suggesting that this test can be an important diagnostic tool for ASA-induced urticaria/angioedema.
