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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445544

RESUMO

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Citoplasma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ácido Fólico/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Células Tumorais Cultivadas
2.
Biochim Biophys Acta Mol Cell Res ; 1868(6): 119016, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744274

RESUMO

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used in the clinical treatment of non-small cell lung cancer (NSCLC) patients with EGFR mutations. Previous studies have shown that Aurora kinase A (AURKA) is overexpressed in a broad spectrum of cancer cells, which can induce epithelial-mesenchymal transition (EMT) and contribute to the occurrence of acquired EGFR-TKI resistance. However, whether the inhibition of AURKA could overcome EGFR-TKI resistance or reverse the EMT in TKI-resistant NSCLC cells remains unclear. In the current study, we established three EGFR-TKI-resistant cell lines and analyzed their expression profiles by RNA sequencing. The results revealed that the EMT pathway is significantly upregulated in the three cell lines with EGFR-TKI resistance. The phosphorylation of AURKA at Thr 288 was also upregulated, suggesting that the activation of AURKA plays an important role in the occurrence of EGFR-TKI resistance. Interestingly, the AURKA inhibitor, alisertib treatment restored the susceptibility of resistant cells to EGFR-TKIs and partially reversed the EMT process, thereby reducing migration and invasion in EGFR-TKI-resistant cells. This study provides evidence that targeting AURKA signaling pathway by alisertib may be a novel approach for overcoming EGFR-TKI resistance and for the treatment of metastatic EGFR-TKIs in NSCLC patients.


Assuntos
Aurora Quinase A/metabolismo , Azepinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Aurora Quinase A/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Receptores ErbB/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Fosforilação/efeitos dos fármacos , Análise de Sequência de RNA/métodos , Regulação para Cima/efeitos dos fármacos
3.
Cancer Res ; 80(20): 4426-4438, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816907

RESUMO

Regulation of the stemness factor, SOX2, by cytokine stimuli controls self-renewal and differentiation in cells. Activating mutations in EGFR are proven therapeutic targets for tyrosine kinase inhibitors (TKI) in lung adenocarcinoma, but acquired resistance to TKIs inevitably occurs. The mechanism by which stemness and differentiation signaling emerge in lung cancers to affect TKI tolerance and lung cancer dissemination has yet to be elucidated. Here, we report that cross-talk between SOX2 and TGFß signaling affects lung cancer cell plasticity and TKI tolerance. TKI treatment favored selection of lung cancer cells displaying mesenchymal morphology with deficient SOX2 expression, whereas SOX2 expression promoted TKI sensitivity and inhibited the mesenchymal phenotype. Preselection of EGFR-mutant lung cancer cells with the mesenchymal phenotype diminished SOX2 expression and TKI sensitivity, whereas SOX2 silencing induced vimentin, but suppressed BCL2L11, expression and promoted TKI tolerance. TGFß stimulation downregulated SOX2 and induced epithelial-to-mesenchymal transdifferentiation accompanied by increased TKI tolerance, which can interfere with ectopic SOX2 expression. SOX2-positive lung cancer cells exhibited a lower dissemination capacity than their SOX2-negative counterparts. Tumors expressing low SOX2 and high vimentin signature were associated with worse survival outcomes in patients with EGFR mutations. These findings provide insights into how cancer cell plasticity regulated by SOX2 and TGFß signaling affects EGFR-TKI tolerance and lung cancer dissemination. SIGNIFICANCE: These findings suggest the potential of SOX2 as a prognostic marker in EGFR-mutant lung cancer, as SOX2-mediated cell plasticity regulated by TGFß stimulation and epigenetic control affects EGFR-TKI tolerance and cancer dissemination.


Assuntos
Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Fatores de Transcrição SOXB1/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Fatores de Transcrição SOXB1/genética , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo
4.
Oncotarget ; 8(32): 53405-53418, 2017 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-28881820

RESUMO

Non-small cell lung cancer (NSCLC) patients tend to develop brain metastases (BM), but the link between BM occurrence and driver mutations in NSCLC is not very clear. We explored whether activating mutations of epidermal growth factor receptors (EGFRs) in exon 19 deletion or L858R predict BM in NSCLC. A retrospective multivariable logistic regression analysis of 384 patients demonstrated that the presence of mutated-EGFRs was associated with overall BM (OR=2.24, P=0.001) compared to that of wild-type EGFR (WT-EGFR). Moreover, the time-to-event analysis model considering death as a competing risk revealed that, irrespective of survival, mutated-EGFRs predicted subsequent BM (SBM) in stage IIIB-IV patients (37.1% vs. 10.6%, HR=2.98, P=0.002) after adjusting for age (HR=2.00, P=0.012), gender, histological subtype, and smoking history. Notably, the younger mutated-EGFR subgroup was at a higher risk for SBM compared to the older WT-EGFR one (58.1% vs.10.9%, HR=6.57, P<0.001). Additionally, EGFR exon 19 deletion, despite having a slightly longer overall survival (20.6 vs. 14.2 months, P=0.368), was comparable to L858R mutation in predicting SBM (39.5% vs. 34.5%, HR=0.91, P=0.770). In vitro, the overexpression of mutated-EGFRs induced morphological changes towards a mesenchymal-like phenotype and promoted mobility in lung cancer cells. Clinically, mutated-EGFR NSCLC displayed a higher proportion of vimentin-positive expression (75.3% vs. 51.2%; P=0.007) and a shorter median time to SBM (23.5 months vs. not reached, P=0.017) than WT-EGFR NSCLC. These results suggest that NSCLC patients carrying mutated-EGFRs may require a higher frequency of brain imaging assessments than those with WT-EGFR to facilitate earlier SBM detection during follow-up.

5.
Cancer Res ; 77(11): 3013-3026, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28381546

RESUMO

Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKI). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma. Cancer Res; 77(11); 3013-26. ©2017 AACR.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Receptores ErbB , Feminino , Humanos , Camundongos , Camundongos Nus , Mutação , Transdução de Sinais
6.
PLoS One ; 10(9): e0137979, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26367274

RESUMO

BACKGROUND: Tumor necrosis factor (TNF)-α and matrix metalloproteinases (MMPs) are elevated in pleural fluids of tuberculous pleuritis (TBP) where pleural mesothelial cells (PMCs) conduct the first-line defense against Mycobacterium tuberculosis (MTB). However, the clinical implication of TNF-α and MMPs in TBP and the response of PMCs to MTB infection remain unclear. METHODS: We measured pleural fluid levels of TNF-α and MMPs in patients with TBP (n = 18) or heart failure (n = 18) as controls. Radiological scores for initial effusion amount and residual pleural fibrosis at 6-month follow-up were assessed. In vitro human PMC experiments were performed to assess the effect of heat-killed M. tuberculosis H37Ra (MTBRa) on the expression of TNF-α and MMPs. RESULTS: As compared with controls, the effusion levels of TNF-α, MMP-1 and MMP-9 were significantly higher and correlated positively with initial effusion amount in patients with TBP, while TNF-α and MMP-1, but not MMP-9, were positively associated with residual pleural fibrosis of TBP. Moreover, effusion levels of TNF-α had positive correlation with those of MMP-1 and MMP-9 in TBP. In cultured PMCs, MTBRa enhanced TLR2 and TLR4 expression, activated ERK signaling, and upregulated TNF-α mRNA and protein expression. Furthermore, knockdown of TLR2, but not TLR4, significantly inhibited ERK phosphorylation and TNF-α expression. Additionally, both MTBRa and TNF-α markedly induced MMP-1 and MMP-9 synthesis in human PMCs, and TNF-α neutralization substantially reduced the production of MMP-1, but not MMP-9, in response to MTBRa stimulation. CONCLUSION: MTBRa activates TLR2/ERK signalings to induce TNF-α and elicit MMP-1 and MMP-9 in human PMCs, which are associated with effusion volume and pleural fibrosis and may contribute to pathogenesis of TBP. Further investigation of manipulation of TNF-α and MMP expression in pleural mesothelium may provide new insights into the mechanisms and rational treatment strategies for TBP.


Assuntos
Células Epiteliais/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 9 da Matriz/imunologia , Mycobacterium tuberculosis/imunologia , Receptor 2 Toll-Like/imunologia , Tuberculose Pulmonar/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pleura/imunologia , Pleura/patologia , Tuberculose Pulmonar/patologia , Regulação para Cima/imunologia
7.
J Thorac Oncol ; 10(5): 793-799, 2015 05.
Artigo em Inglês | MEDLINE | ID: mdl-25668120

RESUMO

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear. METHODS: A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations. RESULTS: One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005). CONCLUSION: Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.


Assuntos
Adenocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento
8.
Biomed Res Int ; 2014: 231012, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24707477

RESUMO

Tumor necrosis factor-(TNF-)-α upregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-α or HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-α-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-α in the presence or absence of the m-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-α-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-α-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/genética , Fator de Necrose Tumoral alfa/genética , Fator 2 Ativador da Transcrição/genética , Células Cultivadas , Fosfatase 1 de Especificidade Dupla/genética , Epitélio/efeitos dos fármacos , Humanos , MAP Quinase Quinase 4/genética , Sistema de Sinalização das MAP Quinases/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , RNA Mensageiro/genética , Transdução de Sinais/genética
9.
Mol Clin Oncol ; 2(2): 252-258, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24649342

RESUMO

Mutations in epidermal growth factor receptor (EGFR) commonly occur in non-small-cell lung cancer (NSCLC) patients characterized by female gender, never-smoker status and adenocarcinoma histology. The aim of this study was to determine whether gender is a confounding factor for EGFR mutations in NSCLC. To elucidate the confounding effect, Pearson's χ2 test and logistic regression models were used to correlate these characteristics with EGFR mutations in 426 NSCLC patients treated at our institutes. Of those 426 NSCLC patients, 47% were females, 57% were non-smokers and 84% had adenocarcinomas. The multivariate logistic regression analysis demonstrated that never-smoker status [odds ratio (OR)=3.49, 95% confidence interval (CI): 1.99-6.13; P<0.001)] and adenocarcinoma (OR=9.43, 95% CI 3.62-24.56; P<0.001) were associated with EGFR mutations; however, gender was not (OR=1.25, 95% CI: 0.73-2.15; P=0.416). Furthermore, gender was not associated with EGFR mutation subtypes (OR=1.19, 95% CI: 0.56-2.50; P=0.650). The frequency of EGFR mutations among females and males was not different in non-smokers (64.8 vs. 55.8%, P=0.204) or ever-smokers (27.8 vs. 24.2%, P=0.775). Therefore, if the assessment for EGFR mutation status was limited to non-smoking females with adenocarcinoma, up to 40% of the patients harboring EGFR mutations would be precluded from the benefit of EGFR inhibitor therapy. Our results indicated that gender is a confounding factor for EGFR mutations in NSCLC and suggested that gender may not be associated with tumorigenesis in NSCLC-harboring EGFR mutations.

10.
PLoS One ; 8(12): e83266, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24376677

RESUMO

INTRODUCTION: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been associated with favorable progression free survival (PFS) in patients with non-small cell lung cancers (NSCLC) harboring EGFR mutations. However, a subset of this population doesn't respond to EGFR-TKI treatment. Therefore, the present study aimed to elucidate survival outcome in NSCLC EGFR-mutant patients who were treated with EGFR TKIs. METHODS: Among the 580 consecutive NSCLC patients who were treated at our facility between 2008 and 2012, a total of 124 treatment-naïve, advanced NSCLC, EGFR-mutant patients treated with EGFR TKIs were identified and grouped into non-responders and responders for analyses. RESULTS: Of 124 patients, 104 (84%) responded to treatment, and 20 (16%) did not; and the overall median PFS was 9.0 months. Notably, the PFS, overall survival (OS) and survival rates were significantly unfavorable in non-responders (1.8 vs. 10.3 months, hazard ratio (HR) = 29.2, 95% confidence interval (CI), 13.48-63.26, P<0.0001; 9.4 vs. 17.3 months, HR = 2.74, 95% CI, 1.52-4.94, P = 0.0008; and 58% vs. 82% in 6, 37% vs. 60% in 12, and 19 vs. 40% at 24 months, respectively). In multivariate analysis, treatment efficacy strongly affected PFS and OS, independent of covariates (HR = 47.22, 95% CI, 17.88-124.73, P<0.001 and HR = 2.74, 95% CI, 1.43-5.24, P = 0.002, respectively). However, none of the covariates except of the presence of EGFR exon 19 deletion in the tumors was significantly associated with better treatment efficacy. CONCLUSIONS: A subset of NSCLC EGFR-mutant patients displayed unfavorable survival despite EGFR TKI administration. This observation reinforces the urgent need for biomarkers effectively predicting the non-responders and for drug development overcoming primary resistance to EGFR TKIs. In addition, optimal therapeutic strategies to prolong the survival of non-responders need to be investigated.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Neoplasias Pulmonares/mortalidade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Éxons , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
11.
Lung Cancer ; 82(2): 319-23, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24018025

RESUMO

PURPOSE: Brain metastases (BM), a common occurrence in non-small cell lung cancer (NSCLC), usually lead to a poor prognosis. Recently, the selection of treatment modalities for BM has modestly improved patient survival and quality of life. Treatment choice is largely based on the number of BM, the presence of BM-related symptoms, and performance status. Therefore, early BM detection is crucial. In this study, we aimed to elucidate the factors associated with BM and identify subgroups of patients at higher risk for BM. METHODS AND PATIENTS: The medical records of 596 consecutive patients with stage I-IV NSCLC were reviewed between January 2006 and November 2011. A multivariate logistic regression (MLR) model was used to identify factors associated with BM. RESULTS: Among 482 eligible stage IIIB/IV NSCLC patients, 173 (36%) experienced BM during their disease course. On MLR analysis, female gender, age < 60 years and adenocarcinoma were associated with BM (OR = 1.71, 95% CI = 1.06-2.75, P = 0.028; OR = 2.11, 95% CI = 1.38-3.22, P = 0.001; and OR = 2.39, 95% CI = 1.16-4.92, P = 0.018, respectively). The actuarial incidence of BM varied widely from 14% to 59% in different subgroups; younger patients with adenocarcinoma tended to experience BM more than older patients with squamous cell carcinoma (OR = 6.88, 95% CI = 2.97-15.94, P < 0.001). Furthermore, the incidence of BM correlated closely with survival after NSCLC diagnosis, and it was 42%, 54% and 64% in patients who survived more than 3, 12 and 24 months, respectively. Notably, the number of BM, the size of the largest BM and the proportion of multiple BM, defined as more than 4 metastatic tumors in brain, were significantly different in NSCLC patients with and without BM-related symptoms or signs (4.0 ± 2.1 vs 2.7 ± 1.9, P < 0.001; 2.6 ± 1.5 vs 1.3 ± 1.0 CM, P < 0.001, and 50% vs 21%, P < 0.001, respectively). CONCLUSION: We found that subgroups of NSCLC patients characterized by younger age, female gender and adenocarcinoma are at higher risks for BM. These findings might be helpful to detect BM earlier and facilitate the design of clinical trials aiming at their prevention.


Assuntos
Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Adulto , Fatores Etários , Idoso , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco
12.
Stem Cells ; 31(12): 2607-19, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23940081

RESUMO

Tumor cells have long been observed to share several biological characteristics with normal stem/progenitor cells; however, the oncogenic mechanisms underlying the lung stem/progenitor cell signaling remain elusive. Here, we report that SOX2, a self-renewal factor in lung stem/progenitor cells, is highly expressed in a subclass of lung cancer cells, the proliferation, survival, and chemoresistance of which are dependent on SOX2 signaling. Overexpression of SOX2 promotes oncogenic phenotypes in lung cancer cells; knockdown of SOX2 attenuated cell proliferation. We observed that SOX2 increased the expression of epidermal growth factor receptor (EGFR), and EGFR activation further upregulated SOX2 levels, forming a positive feedback loop. SOX2 expression promoted chemoresistance, and silencing of SOX2 perturbed mitochondrial function, causing marked apoptosis and autophagy. SOX2 induced BCL2L1, the ectopic expression of which rescued the effects of SOX2 silencing on apoptosis, autophagy, and mitochondrial function. SOX2 promoted tumor formation, along with increased cell proliferation in a xenograft mouse model. SOX2 expression is associated with poor prognosis in lung cancer patients; moreover, SOX2, EGFR, and BCL2L1 expression levels were significantly correlated in lung tumors. Our findings support the emerging role of SOX2 in cell proliferation and survival by eliciting oncogenic EGFR and BCL2L1 signaling with potential applications as a prognosis marker and a therapeutic target in lung cancer.


Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fatores de Transcrição SOXB1/metabolismo , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/biossíntese , Receptores ErbB/genética , Receptores ErbB/metabolismo , Técnicas de Silenciamento de Genes , Inativação Gênica , Xenoenxertos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , Paclitaxel/farmacologia , Fatores de Transcrição SOXB1/genética , Transdução de Sinais , Análise de Sobrevida , Proteína bcl-X/metabolismo
13.
Clin Lung Cancer ; 14(6): 719-25, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23891241

RESUMO

INTRODUCTION: Recent advances in the treatment of NSCLC highlight the importance of distinguishing NSCLC subtypes and genotypes. We aimed to determine whether histological specimens obtained from computed tomography (CT)-guided biopsy are suitable for specific subtyping and epidermal growth factor receptor (EGFR) analyses of NSCLC. PATIENTS AND METHODS: The clinicohistological data of 332 consecutive patients undergoing 352 CT-guided biopsies for lung lesions between January 2007 and December 2011 were retrospectively analyzed. Additionally, NSCLC specimens were examined for the suitability of EGFR mutational testing. RESULTS: Of 209 specimens diagnosed as NSCLC, 197 (94.3%) were specifically subtyped into adenocarcinoma (n = 164; 78.5%), squamous cell carcinoma (n = 27; 12.9%) and other subtypes (n = 6; 2.9%). The rate of NSCLC not otherwise specified (NOS) was 5.7%, and the diagnosis of NSCLC-NOS was significantly associated with the poor differentiation of cancer (adjusted odds ratio, 6.17; 95% confidence interval, 1.62-23.55; P = .008). Of 134 histological tumor specimens submitted for EGFR molecular testing, 132 (98.5%) were suitable for analyses, and 130 of them (98.5%) showed conclusive results, revealing 59.8% (n = 79) with EGFR exon mutation(s). The sensitivity, specificity, and positive and negative predictive values of CT-guided biopsy in patients with malignancy were 92.2%, 100%, 100%, and 74.1%, respectively. Six percent (n = 21) of total lung biopsies led to pneumothorax requiring chest drainage, and no procedure-related fatality was observed. CONCLUSION: Small tumor specimens obtained with CT-guided needle lung biopsy are suitable for specific subtyping and EGFR analyses of NSCLC, thus providing critical information for personalized therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Genes erbB-1/genética , Biópsia Guiada por Imagem , Neoplasias Pulmonares/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Análise Mutacional de DNA , Estudos de Viabilidade , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Adulto Jovem
14.
Lung Cancer ; 81(3): 455-461, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23871711

RESUMO

INTRODUCTION: Brain metastases (BM) commonly occur in patients with lung adenocarcinoma and usually lead to a poor prognosis and quality of life despite of radiotherapy. Epidermal growth factor receptor (EGFR) mutations have been widely demonstrated to be a predictive and prognostic factor for lung adenocarcinoma, however, its impact on BM from lung adenocarcinoma remains inconclusive. The present study aimed to elucidate the predictive role of EGFR mutations in BM treatment response and survival after BM in patients with lung adenocarcinoma. MATERIAL AND METHODS: From January 2006 through February 2012, 180 of 505 lung adenocarcinoma patients developed BM during their disease course were reviewed for eligibility, and 139 patients, including 89 EGFR-mutant and 50 EGFR wild-type patients, were identified for analysis. RESULTS: Of the patients eligible for evaluation of treatment response, up to 85% received radiotherapy and the remaining took EGFR tyrosine kinase inhibitors (TKIs) as the front modality for BM. EGFR-mutant patients, compared with EGFR wild-type patients, had significantly greater intracranial treatment response of BM (84% vs. 48%, P = 0.002), experienced higher therapeutic efficacy to radiotherapy (86% vs. 52%, P = 0.005), and had longer median survival after BM diagnosis (13.2 vs. 6.8 months, P < 0.001). Furthermore, EGFR mutation (P = 0.002) and performance status (P = 0.009) were independently associated with BM treatment response. Additionally, EGFR mutation (P = 0.005), good performance status (P < 0.001) and absence of extracranial metastases (P=0.033) correlated with better survival. CONCLUSION: EGFR mutation is an independent predictive factor for both BM treatment response and survival after BM in patients with lung adenocarcinoma. Further prospective studies on incorporation of EGFR mutation status into therapeutic strategy and survival prediction system for lung adenocarcinoma with BM are warranted.


Assuntos
Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Antineoplásicos/administração & dosagem , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Radiografia , Resultado do Tratamento , Carga Tumoral
15.
PLoS One ; 8(1): e53169, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23308155

RESUMO

OBJECTIVE: To investigate the relationship among angiogenic cytokines, fibrinolytic activity and effusion size in parapneumonic effusion (PPE) and their clinical importance. METHODS: From January 2008 through December 2010, 26 uncomplicated (UPPE) and 38 complicated (CPPE) PPE were studied. Based on chest ultrasonography, there were non-loculated in 30, uni-loculated in 12, and multi-loculated effusions in 22 patients. The effusion size radiological scores, and effusion vascular endothelial growth factor (VEGF), interleukin (IL)-8, plasminogen activator inhibitor type-1 (PAI-1) and tissue type plasminogen activator (tPA) were measured on admission. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up. RESULTS: The effusion size and effusion VEGF, IL-8 and PAI-1/tPA ratio were significantly higher in CPPE than in UPPE, and significantly higher in multi-loculated PPE than in non-locualted and uni-loculated PPE, respectively. VEGF (cutoff value 1975 pg/ml) and IL-8 (cutoff value 1937 pg/ml) seemed best to discriminate between UPPE and CPPE. VEGF, IL-8 and effusion size correlated positively with PAI-1/tPA ratio in both UPPE and CPPE. Moreover, the level of VEGF, but not IL-8, correlated positively with effusion size in all patients (r = 0.79, p<0.001) and in UPPE (r = 0.64, p<0.001) and CPPE (r = 0.71, p<0.001) groups. The patients with higher VEGF or greater effusion were prone to have medical treatment failure (n = 10; VEGF, odds ratio 1.01, p = 0.02; effusion size, odds ratio 1.26, p = 0.01). Additionally, ten patients with RPT had larger effusion size and higher levels of VEGF and PAI-1/tPA ratio than did those without. CONCLUSIONS: In PPE, VEGF and IL-8 levels are valuable to identify CPPE, and higher VEGF level or larger effusion is associated with decreased fibrinolytic activity, development of pleural loculation and fibrosis, and higher risk of medical treatment failure.


Assuntos
Interleucina-8/análise , Inibidor 1 de Ativador de Plasminogênio/análise , Pleura/patologia , Derrame Pleural/patologia , Ativador de Plasminogênio Tecidual/análise , Fator A de Crescimento do Endotélio Vascular/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Citocinas , Feminino , Fibrinólise , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pleura/efeitos dos fármacos , Derrame Pleural/complicações , Derrame Pleural/tratamento farmacológico , Pneumonia/complicações , Resultado do Tratamento
16.
Chem Biol Interact ; 197(1): 23-30, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22450442

RESUMO

Pycnidione, a small tropolone first isolated from the fermented broth of Theissenia rogersii 92031201, exhibits antitumor activities through an undefined mechanism. The present study evaluated the effects and mechanisms of pycnidione on the growth and death of A549 human lung cancer cells. Pycnidione significantly inhibited the proliferation of A549 cells in a concentration-dependent manner, with a 50% growth inhibition (GI(50)) value of approximately 9.3nM at 48h. Pycnidione significantly decreased the expression of cyclins D1 and E and induced G(1)-phase cell cycle arrest and a subsequent increase in the sub-G(1) phase population. Pycnidione also markedly reduced the expression of survivin and activated caspase-8 and -3, increased reactive oxygen species (ROS) generation, caused the collapse of the mitochondrial membrane potential (MMP), and enhanced PAI-1 production, thus triggering apoptosis in the A549 cells. Taken together, pycnidione exerts anti-proliferative effects on human lung cancer cells through the induction of cell cycle arrest and apoptosis. Therefore, testing of its effects in vivo is warranted to evaluate its potential as a therapeutic agent against lung cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Fungos/química , Neoplasias Pulmonares/tratamento farmacológico , Tropolona/química , Tropolona/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
Am J Respir Cell Mol Biol ; 46(4): 437-45, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22033265

RESUMO

Plasminogen activator inhibitor-1 (PAI-1), primarily up-regulated by transforming growth factor (TGF)-ß, is essential in the development of fibrosis. Histone deacetylase (HDAC) was shown to modulate gene expression and fibrogenesis in various tissues. However, the implications of HDAC in terms of PAI-1 expression and pleural fibrosis remain unclear. In this study, we examined the effects of m-carboxycinnamic acid bis-hydroxamide (CBHA), a hybrid-polar HDAC inhibitor, on the TGF-ß1-induced expression of PAI-1 in a human pleural mesothelial cell line (MeT-5A). MeT-5A cells were treated with TGF-ß1 in the presence or absence of CBHA. We assayed the expression and stability of PAI-1 mRNA and protein, PAI-1 promoter activity, the activation of Smad signaling, the protein-protein interactions of Smads with transcriptional cofactors Sp1 and coactivator p300, and the expression of the mRNA-stabilizing protein nucleolin. The results indicate that CBHA significantly inhibited TGF-ß1-induced PAI-1 mRNA and protein expression, and attenuated PAI-1 promoter activity in MeT-5A cells. CBHA abrogated TGF-ß1-induced Smad4 nuclear translocation, but not Smad2/3 activation. Furthermore, the association of Smad4 with p300, but not with Sp1, was disrupted by CBHA. Alternatively, CBHA suppressed TGF-ß1-induced nucleolin expression, and thereby destabilized PAI-1 mRNA and decreased PAI-1 protein concentrations. These findings suggest that the inhibition of HDAC activity by CBHA may attenuate PAI-1 expression through the modulation of cellular signaling at multiple levels. Given the down-regulating effect of CBHA on PAI-1 expression, HDAC inhibitors should be tested further in animal models as potential therapeutic agents for pleural fibrosis.


Assuntos
Cinamatos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Pleura/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ribonucleoproteína Nuclear Heterogênea D0 , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo D/metabolismo , Histonas/metabolismo , Humanos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Inibidor 1 de Ativador de Plasminogênio/genética , Pleura/citologia , Regiões Promotoras Genéticas , Processamento Pós-Transcricional do RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Proteína Smad4/metabolismo , Fator de Transcrição Sp1/genética , Fator de Transcrição Sp1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Fatores de Transcrição de p300-CBP/genética , Fatores de Transcrição de p300-CBP/metabolismo
18.
Respirology ; 15(6): 1001-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20646242

RESUMO

BACKGROUND AND OBJECTIVE: Therapeutic thoracentesis (TT) is required in patients with refractory pleural effusions and impaired oxygenation. In this study, the relationship between pleural space elastance (PE) and changes in oxygenation after TT was investigated in ventilated patients with heart failure and transudative pleural effusions. METHODS: Twenty-six mechanically ventilated patients with heart failure and significant transudative effusions, who were undergoing TT, were studied. The effusion was drained as completely as possible, with monitoring of pleural liquid pressure (Pliq) and chest symptoms. The volume of effusion removed, the changes in Pliq during TT, PE and arterial blood gases before and after TT were recorded. RESULTS: The mean volume of effusion removed was 1011.9 +/- 58.2 mL. The mean Pliq decreased from 14.5 +/- 1.0 to 0.1 +/- 1.5 cm H(2)O after TT, and the mean PE was 15.3 +/- 1.8 cm H(2)O/L. TT significantly increased the mean ratio of PaO(2)/fraction of inspired oxygen (FiO(2)) from 243.2 +/- 19.9 to 336.0 +/- 17.8 mm Hg (P < 0.0001). The changes in PaO(2)/FiO(2) ratio after TT were inversely correlated with PE (r = -0.803, P < 0.0001). The 14 patients (54%) with normal PE (14.5 cm H(2)O/L). CONCLUSIONS: Measurement of PE during TT may be valuable for predicting improvement in oxygenation in ventilated patients with heart failure and pleural effusions. Patients with lower PE showed greater improvement in oxygenation after TT.


Assuntos
Exsudatos e Transudatos , Insuficiência Cardíaca/terapia , Oxigênio/sangue , Paracentese , Cavidade Pleural/fisiopatologia , Derrame Pleural/terapia , Respiração Artificial , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino
19.
Am J Emerg Med ; 26(3): 384.e3-5, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18358975

RESUMO

Glyphosate-surfactant is used extensively as a nonselective herbicide. Suicidal attempts with glyphosate-surfactant herbicide (GlySH) has been encountered with increasing frequency. The effect of GlySH intoxication often involves multiple systems. We report a case of a severely intoxicated man who developed chemical pneumonitis and respiratory failure after suicidal ingestion of GlySH. Acute pancreatitis, which was never covered by any previous case reports, developed in the first day, and the symptom persisted for 10 days during hospitalization.


Assuntos
Glicina/análogos & derivados , Herbicidas/envenenamento , Pancreatite/induzido quimicamente , Doença Aguda , Idoso de 80 Anos ou mais , Glicina/envenenamento , Humanos , Masculino , Nutrição Parenteral , Tentativa de Suicídio , Tomografia Computadorizada por Raios X
20.
Chang Gung Med J ; 29(6): 568-75, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17302220

RESUMO

BACKGROUND: House dust mites (HDM) are one of the major risk factors for the development of bronchial asthma. The percentage of sensitization to HDM was reported to be 71.9% in Taipei City. In southwestern Taiwan, the percentage of sensitization to HDM has not been estimated. We retrospectively reviewed the medical records of asthmatic patients treated at the Chiayi branch of Chang Gung Memorial Hospital to investigate the percentage and associations with demographic characteristics. METHODS: We analyzed the data of 194 asthmatic patients diagnosed between January 2003 and July 2005. Sensitization to indoor allergens was identified by serum specific immunoglobulin E (IgE) of ImmunoCAP. Demographic characteristics of age, gender and residence were evaluated for associations with allergic sensitization. RESULTS: The percentage of sensitization to HDM was only 45.9% in patients in southwestern Taiwan. The majority of the studied group were elderly patients. The age variable significantly influenced the percentage of sensitization to HDM and cockroaches (p < 0.001 in both comparisons). The gender variable contributed to sensitization to cockroaches only (p = 0.002). For residential variables, there was no significant difference in the percentage of allergic sensitization to all tested indoor allergens among distinct areas of southwestern Taiwan. CONCLUSION: The percentage of sensitization to HDM in asthmatic patients residing in southwestern Taiwan was lower than that in metropolitan patients. This discrepancy might be attributed to the larger proportion of aged patients.


Assuntos
Asma/imunologia , Hipersensibilidade/epidemiologia , Pyroglyphidae/imunologia , Adulto , Fatores Etários , Idoso , Animais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Taiwan/epidemiologia
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