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BACKGROUND: Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates prompt the identification of the HER2-low subtype. However, the biological significance of HER2-low expression in breast cancer is unclear. METHODS: Clinical and genomic data of 579 metastatic breast cancer patients were reviewed from our next-generation sequencing (NGS) database and genomic analysis of early breast cancer patients from TCGA was also analyzed. FINDINGS: First, the clinicopathological characteristics of HER2-low patients were profoundly influenced by HR status and no difference of prognosis was observed between HER2-low and HER2-zero patients when paired by HR status, but notably HER2-low patients showed similar metastatic patterns to HER2-positive patients in the HR-positive (HR+ ) subgroup, with more brain and initial lung metastases and more cases of de novo stage IV breast cancer than HER2-zero patients. Second, among patients with primary HER2-low or HER2-zero tumors, the discordance of HER2 status between primary and metastatic tumors was significant, with 48.4% of patients with HER2-zero primary tumors exhibiting HER2-low phenotype in metastatic tumors in the HR+ subgroup. Third, within HR+ and HR-negative subtypes, HER2-low and HER2-zero tumors showed no substantial differences in mutation alterations and copy number variations. Forth, germline BRCA2 mutations were observed only in HER2-low patients in our NGS database, especially in HR+ HER2-low tumors. Finally, three molecular subtypes based on genomic alterations in HER2-low breast cancer were identified, which provided novel insights into heterogeneity in HER2-low breast cancer. CONCLUSIONS: After correcting for HR expression, only marginal differences in clinical and molecular phenotypes were determined between HER2-low and HER2-zero breast cancer. Therefore, HER2-low breast cancer is insufficient to be defined as a distinct molecular entity, but rather a heterogenous disease.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Prognóstico , GenômicaRESUMO
PURPOSE: Triple-negative breast cancer is characterized by fast progression with high possible for metastasis and poor survival. Dysfunction of microRNAs plays an important role in the initiation and progression of cancer. Our previous microRNA-seq data indicated the downregulation of miR-331-3p in triple-negative breast cancer tissues compared with that of the noncancer tissues. However, the function of miR-331-3p in triple-negative breast cancer remains largely unknown. Herein, the involvement of miR-331-3p in triple-negative breast cancer was investigated and the therapeutic potential of miR-331-3p was also explored. METHODS: Real-time quantitative polymerase chain reaction was performed to detect the expression of miR-331-3p in triple-negative breast cancer tissues and cell lines. The cell proliferation was determined by the cell counting kit-8 assay. Apoptosis of triple-negative breast cancer cells was examined by annexin V/propidium iodide staining. miRDB database was used to predict the potential targets of miR-331-3p. Western blot was performed to examine the expression of the target protein. RESULTS: miR-331-3p was significantly downregulated in triple-negative breast cancer tissues and cell line. Lower miR-331-3p expression was significantly correlated with the tumor size, TNM stage, and lymph node metastasis of patients with triple-negative breast cancer. Functional experiments showed that the overexpression of miR-331-3p inhibited the proliferation and increased apoptosis of triple-negative breast cancer cells. Neuropilin-2 was identified as a target of miR-331-3p, which harbored binding site of miR-331-3p in its 3'-untranslated region. Overexpression of miR-331-3p decreased the messenger RNA and protein levels of neuropilin-2 in triple-negative breast cancer cells. Restoration of neuropilin-2 partially reversed the inhibitory effects of miR-331-3p on the proliferation of triple-negative breast cancer cells. CONCLUSIONS: Our results demonstrated the novel function of miR-331-3p/neuropilin-2 signaling in regulating the malignant behaviors of triple-negative breast cancer cells, which suggested miR-331-3p as a potential target for the treatment of triple-negative breast cancer.
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Apoptose , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neuropilina-2/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Humanos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with both epidermal growth factor receptor (EGFR) positive mutation and B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism had a poor clinical response to EGFR-tyrosine kinase inhibitors (TKIs). The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus chemotherapy versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism. METHODS: A retrospective, non-randomized analysis was conducted. BIM deletion polymorphism was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from peripheral blood cells. Clinical characteristics, overall survival (OS), progress-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared between EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy group. RESULTS: 65 patients were enrolled. 36 of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% vs. 38.9%, Pâ¯=â¯0.046). Median PFS was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 vs 4.7â¯m; Pâ¯=â¯0.008). Median OS was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 vs 14.2â¯m; Pâ¯=â¯0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone. CONCLUSION: EGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged PFS and numerically longer OS in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Proteína 11 Semelhante a Bcl-2/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/genética , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Drug resistance remains a major challenge in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Bcl-2-like protein 11 (BIM), a B-cell lymphoma 2 family pro-apoptotic protein, is a prime target for specific anti-cancer therapeutics. However, the epigenetic regulation of BIM in non-small cell lung cancer (NSCLC) cell lines and patients with NSCLC in association with EGFR-TKI resistance requires investigation. Methylation-specific PCR (MSP), pyrosequencing, and nested quantitative (q)-MSP were conducted to explore the methylation status of BIM in NSCLC cell lines. In addition, the methylation profile of BIM in patients with NSCLC was assessed by nested q-MSP using circulating free DNA. Cell lines, treated with methylation inhibitor 5-Aza-2'-deoxycytidine (AZA) or histone deacetylation inhibitor trichostatin A (TSA) prior to gefitinib treatment, were examined for BIM gene expression and resistance to gefitinib. All cell lines used in the present study presented with hypo-methylated BIM. Treatment with AZA had no effect on BIM RNA expression in PC9 cells or the gefitinib-resistant cell lines PC9/R and PC9/G2, nor did it reverse their resistance to gefitinib. In contrast, TSA treatment produced the opposite result. In the present study, 25 (78.1%) patients with hypo-methylated BIM and 7 patients (21.9%) with partial or hyper-methylated BIM were identified. The clinicopathological data revealed a random hypo-methylated BIM distribution amongst patients with NSCLC. In the overall study group and EGFR mutant group, hypo-methylated BIM carriers presented with no significant differences in progression free survival compared with patients with partial or hyper-methylated BIM. All cell lines in the present study and the majority of patients with NSCLC carried hypo-methylated BIM. Histone deacetylation, as opposed to promoter methylation, may contribute to the epigenetic silencing of BIM and lead to EGFR TKI resistance in NSCLC.
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BACKGROUND: A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. RESULTS: In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. MATERIALS AND METHODS: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. CONCLUSIONS: In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.
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Proteína 11 Semelhante a Bcl-2/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Mutação , Polimorfismo Genético , Resultado do TratamentoRESUMO
The aim of this study was to explore the role of long non-coding RNA UCA1 (urothelial cancer-associated 1) in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). In our study, UCA1 expression was significantly increased in lung cancer cells and patients with acquired resistance to EGFR-TKIs. Over-expression of UCA1 was significantly associated with a shorter progression-free survival (PFS) [13.0 vs. 8.5 months, P < 0.01] in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (10.5 vs. 12.0 months, P = 0.778), but in patients with non-T790M (19.0 vs. 9.0 months, P = 0.023). UCA1 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition (EMT). The mTOR inhibitor was effective in UCA1-expressing cell PC9/R. Inhibiting mTOR could change the expression of UCA1, although there was no significant difference. In conclusion, the influence of over-expression of UCA1 on PFS for patients with acquired resistance to EGFR-TKIs was from the subgroup with non-T790M mutation. UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.
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Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/química , RNA Longo não Codificante/genética , Animais , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Transição Epitelial-Mesenquimal , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Nus , Análise Multivariada , Mutação , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Regulação para CimaRESUMO
BACKGROUND: POTEE (POTE ankyrin domain family, member E) is a newly identified cancer-testis antigen that has been found to be expressed in a wide variety of human cancers including cancers of the colon, prostate, lung, breast, ovary, and pancreas. AIM: To measure the serum levels of POTEE in patients with non-small-cell lung cancer (NSCLC) and to explore the clinical significance of POTEE in NSCLC. PATIENTS AND METHODS: 104 NSCLC patients, 66 benign lung disease patients and 80 healthy volunteers were enrolled in this study from May 2013 to February 2014. Serum POTEE levels were measured using enzyme-linked immunosorbent assay (ELISA). Numerical variables were recorded as means ± standard deviation (SD) and analyzed by independent t tests. Categorical variables were calculated as rates and were analyzed using a χ2 test or Fisher's exact test. Survival curves were estimated and compared using the Kaplan-Meier method and log-rank tests. RESULTS: Serum POTEE levels were significantly higher in NSCLC patients than in benign lung disease patients and healthy controls (mean ± SD [pg/ml], 324.38± 13.84 vs. 156.93 ± 17.38 and 139.09 ± 15.80, P<0.001) and were significantly correlated with TNM stage. Survival analysis revealed that patients with low serum POTEE had longer progression-free survival (PFS) than those with high serum POTEE (P=0.021). Cox multivariate analysis indicated that POTEE was an independent prognostic factor of progression-free survival (P =0.009, hazard ratio, 2.440). CONCLUSIONS: Serum POTEE level in NSCLC patients is associated with TNM stage and is a potential prognostic factor.
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Antígenos de Neoplasias/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/diagnóstico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Resultado do TratamentoRESUMO
The application of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is limited by drug resistance in non-small cell lung cancer (NSCLC). Long non-coding RNAs (lncRNAs) are known to be involved in tumor development and metastasis, as well as chemotherapy resistance. To gain insight into the molecular mechanisms of EGFR-TKIs resistance, EGFR-TKIssensitive and resistant human lung cancer cells were analyzed by lncRNA microarray. In the present study, we found a total of 22,587 lncRNAs expressed in lung cancer cells. Of these, the expression level of 1,731 lncRNAs was upregulated >2-fold compared with gefitinib-sensitive cells while that of 2,936 was downregulated. Bioinformatics analysis (GO and pathway analyses) revealed that some classical pathways participating in cell proliferation and apoptosis were aberrantly expressed in these cells (P-value cut-off was 0.05). Enhancer-like lncRNAs and their nearby coding genes were analyzed. Six lncRNAs were identified as potential enhancers. Several lncRNAs were validated in lung cancer cell lines using RT-qPCR. To the best of our knowledge, the results showed for the first time that differentially expressed lncRNAs responded to EGFR-TKIs resistance in NSCLC cells. LncRNAs may therefore be novel candidate biomarkers and potential targets for EGFR-TKIs therapy in the future.
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Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/metabolismo , RNA Longo não Codificante/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase , RNA/metabolismoRESUMO
BACKGROUND: Since cancer stem cells exhibit embryonic-like self-renewal characteristics and malignant behavior, including drug resistance and metastasis, they may be the origin of tumorigenesis and cancer recurrence. Cancer cell stemness is also highly relevant to cancer in hypoxic environments. METHODS: In our study, we used cobalt dichloride (CoCl2) to create a hypoxic environment for lung adenocarcinoma A549 cells and the cisplatine-resistant cell line A549/DDP. The cancer stem-like CD166 positive population and the cells' stemness were detected by flowcytometry and quantitative real-time PCR after separation using magnetic antibodies. Drug resistance to cisplatine, docetaxel and pemetrexed was also measured. Finally, a tissue array was used to analyze the relationship between hypoxia-induced stemness and overall survival after radical surgery. RESULTS: Data showed that chemical-induced hypoxia changed cell stemness by enhancing stem cell transcription factors and markers of chemotherapeutic drug resistance. The CD166-positive cancer stem cell-like population showed greater drug resistance than the CD166-negative cells. Tissue array studies also suggested a poorer prognosis for patients whose tissue expressed higher CD166 levels. CONCLUSION: Our findings indicate that chemical hypoxia may augment cancer cell stemness and drug resistance in CD166-positive stem cells. Therefore, targeting the stem-like cell population, especially CD166-positive cells, may represent a novel therapeutic strategy to treat lung cancer.
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Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Células-Tronco Neoplásicas/metabolismo , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores , Hipóxia Celular/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunofenotipagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sobrevida , Adulto JovemRESUMO
Several randomized trials have demonstrated non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations can achieve favorable clinical outcomes on treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation is considered as a predictive marker for efficacy of EGFR-TKIs in NSCLC. Here we show miR-200c overexpression was correlated with the epithelial phenotype and sensitivity to gefitinib in EGFR wild-type NSCLC cell lines. Up-regulated miR-200c could regain the sensitivity to gefitinib in the EGFR wild-type cell lines and miR-200c could regulate epithelial to mesenchymal transition through PI3K/AKT and MEK/ERK pathways. NSCLC patients at advanced stage (N=150) who received EGFR-TKIs (gefitinib or erlotinib) as second- or third-line therapy from September 2008 to December 2012 were included in the study. In 66 NSCLC patients with wild-type EGFR, high levels of miR-200c expression was associated with higher disease control rate (DCR), longer progression-free survival (PFS) and longer overall survival (OS) compared with low miR-200c expression subgroup. In the subgroup with EGFR mutation, the trend remained the same but not statistically significant. Overall, these findings indicated that miR-200c might be a predictive biomarker for sensitivity to EGFR-TKIs in advanced NSCLC patients with wild-type EGFR.
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Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , Idoso , Antineoplásicos/farmacologia , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
OBJECTIVE: It is important to analyze and track Epidermal Growth Factor Receptor (EGFR) mutation status for predicting efficacy and monitoring resistance throughout EGFR-tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC) patients. The objective of this study was to determine the feasibility and predictive utility of EGFR mutation detection in peripheral blood. METHODS: Plasma, serum and tumor tissue samples from 164 NSCLC patients were assessed for EGFR mutations using Amplification Refractory Mutation System (ARMS). RESULTS: Compared with matched tumor tissue, the concordance rate of EGFR mutation status in plasma and serum was 73.6% and 66.3%, respectively. ARMS for EGFR mutation detection in blood showed low sensitivity (plasma, 48.2%; serum, 39.6%) but high specificity (plasma, 95.4%; serum, 95.5%). Treated with EGFR-TKIs, patients with EGFR mutations in blood had significantly higher objective response rate (ORR) and insignificantly longer progression-free survival (PFS) than those without mutations (ORR: plasma, 68.4% versus 38.9%, P = 0.037; serum, 75.0% versus 39.5%, P = 0.017; PFS: plasma, 7.9 months versus 6.1 months, P = 0.953; serum, 7.9 months versus 5.7 months, P = 0.889). In patients with mutant tumors, those without EGFR mutations in blood tended to have prolonged PFS than patients with mutations (19.7 months versus 11.0 months, P = 0.102). CONCLUSIONS: EGFR mutations detected in blood may be highly predictive of identical mutations in corresponding tumor, as well as showing correlations with tumor response and survival benefit from EGFR-TKIs. Therefore, blood for EGFR mutation detection may allow NSCLC patients with unavailable or insufficient tumor tissue the opportunity to benefit from personalized treatment. However, due to the high false negative rate in blood samples, analysis for EGFR mutations in tumor tissue remains the gold standard.
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BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have EGFR mutations. Recent studies have indicated that some patients with positive mutations were refractory to EGFR TKIs if they harbored a B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (Bim) deletion polymorphism. The objective of the current work was to retrospectively study the Bim deletion polymorphism in Chinese patients with NSCLC and its correlation with the efficacy of EGFR TKIs. METHODS: Distribution of the Bim polymorphism was detected using polymerase chain reaction analysis and direct sequencing of DNA from peripheral neutrophils in samples from 352 patients with NSCLC. Of the 352 patients, 166 who received TKI therapy and had an activating mutation identified were involved in further analysis. Progression-free survival (PFS) was the primary endpoint of the subsequent analyses, and the incidence of the Bim polymorphism and its relation to clinical benefit from EGFR TKIs also were investigated. RESULTS: In total, 45 of 352 patient samples (12.8%) had the Bim deletion polymorphism, which was distributed randomly with regard to various clinical characteristics. In patients with EGFR mutations who received treatment with TKIs, the median PFS and the median objective response rate were 4.7 months and 25%, respectively, for those with the Bim deletion polymorphism versus 11 months (P = .003) and 66% (P = .001), respectively, for those with wild-type Bim. Cox regression analysis identified Bim status (P = .016) and sex (P = .002) as independent factors predicting clinical benefit from EGFR TKIs in patients with EGFR-mutated NSCLC. CONCLUSIONS: The incidence of the Bim deletion polymorphism was approximately 13% in this study, and it was associated with a poor clinical response to EGFR TKIs in patients who had NSCLC with EGFR mutations.
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Proteínas Reguladoras de Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 11 Semelhante a Bcl-2 , Carcinoma Pulmonar de Células não Pequenas/enzimologia , China , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Deleção de Genes , Genótipo , Humanos , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Estudos RetrospectivosRESUMO
OBJECTIVES: To discuss the predictive factors of postoperative survival for non small cell lung carcinoma (NSCLC) patients with clinical N0 stage but postoperative pathological N2 stage (cN0-pN2). METHODS: From January 1, 2005, to December 31, 2009, the clinical data of NSCLC patients with cN0-pN2 after radical surgery were retrospectively collected, and their survival information was collected through follow-up. The expiration date for follow-up was December 31, 2011. The predictive factors of postoperative survival for NSCLC patients with unexpected mediastinal lymph node metastasis were analyzed using Cox proportional hazards regression. RESULTS: A total of 263 patients were enrolled. The follow-up rate was 91.63%. The overall 1-, 3-, and 5-year survival rates were 94.6, 55.2, and 26.3%, respectively. Video-assisted thoracotomy surgery (VATS; odds ratio [OR] 0.659; 95% confidence interval [CI] 0.469 to 0.927; p = 0.017), multiple stations of metastatic mediastinal lymph nodes (OR 1.605; 95% CI 1.180 to 2.183; p = 0.003), and no adjuvant chemotherapy (OR 1.576; 95% CI 1.105 to 2.246; p = 0.012) were independent predictive factors for unexpected N2 patients. The median survival after VATS was superior to that after thoracotomy for patients with a single station of metastatic mediastinal lymph node (48.45 m vs 37.34 m, p = 0.018). The median survival without any adjuvant chemotherapy was inferior to that after adjuvant chemotherapy for patients with multiple stations of metastatic mediastinal lymph nodes (20.32 m vs 31.55 m, p = 0.001). CONCLUSION: The postoperative survival for NSCLC patients with cN0-pN2 was related to operational method, adjuvant chemotherapy, and the number of metastatic mediastinal lymph node stations. Patients with a single station of metastatic mediastinal lymph node are likely to benefit from VATS, whereas patients with multiple stations of metastatic mediastinal lymph nodes are likely to benefit from adjuvant chemotherapy.
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Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/mortalidade , Pneumonectomia/métodos , Idoso , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/cirurgia , China/epidemiologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Metástase Linfática , Masculino , Mediastino , Estadiamento de Neoplasias , Período Pós-Operatório , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Our pilot study using miRNA arrays found that miRNA-29c (miR-29c) is differentially expressed in the paired low-metastatic lung cancer cell line 95C compared to the high-metastatic lung cancer cell line 95D. Bioinformatics analysis shows that integrin ß1 and matrix metalloproteinase 2 (MMP2) could be important target genes of miR-29c. Therefore, we hypothesized that miR-29c suppresses lung cancer cell adhesion to extracellular matrix (ECM) and metastasis by targeting integrin ß1 and MMP2. The gain-of-function studies that raised miR-29c expression in 95D cells by using its mimics showed reductions in cell proliferation, adhesion to ECM, invasion and migration. In contrasts, loss-of-function studies that reduced miR-29c by using its inhibitor in 95C cells promoted proliferation, adhesion to ECM, invasion and migration. Furthermore, the dual-luciferase reporter assay demonstrated that miR-29c inhibited the expression of the luciferase gene containing the 3'-UTRs of integrin ß1 and MMP2 mRNA. Western blotting indicated that miR-29c downregulated the expression of integrin ß1 and MMP2 at the protein level. Gelatin zymography analysis further confirmed that miR-29c decreased MMP2 enzyme activity. Nude mice with xenograft models of lung cancer cells confirmed that miR-29c inhibited lung cancer metastasis in vivo, including bone and liver metastasis. Taken together, our results demonstrate that miR-29c serves as a tumor metastasis suppressor, which suppresses lung cancer cell adhesion to ECM and metastasis by directly inhibiting integrin ß1 and MMP2 expression and by further reducing MMP2 enzyme activity. The results show that miR-29c may be a novel therapeutic candidate target to slow lung cancer metastasis.
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Matriz Extracelular/patologia , Integrina beta1/genética , Neoplasias Pulmonares/patologia , Metaloproteinase 1 da Matriz/genética , MicroRNAs/genética , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Bovinos , Adesão Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Feminino , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , RatosRESUMO
OBJECTIVES: This study compares early and late outcomes for treatment by video-assisted thoracic surgery (VATS) versus treatment by thoracotomy for clinical N0, but post-operatively unexpected, pathologic N2 disease (cN0-pN2). METHODS: Clinical records of patients with unexpected N2 non-small cell lung cancer (NSCLC) who underwent VATS were retrospectively reviewed, and their early and late outcomes were compared to those of patients undergoing conventional thoracotomy during the same period. RESULTS: VATS lobectomy took a longer time than thoracotomy (P < 0.001), but removal of thoracic drainage and patient discharge were earlier for patients in the VATS group (P < 0.001). There was no difference in lymph node dissection, mortality and morbidity between the two groups (P > 0.05). The median follow-up time for 287 patients (89.7%) was 37.0 months (range: 7.0-69.0). The VATS group had a longer survival time than for the thoracotomy group (median 49.0 months vs. 31.7 months, P < 0.001). The increased survival time of the VATS group was due to patients with a single station of N2 metastasis (P = 0.001), rather than to patients with multiple stations of N2 metastasis (P = 0.225). CONCLUSIONS: It is both feasible and safe to perform VATS lobectomy on patients with unexpected N2 NSCLC. VATS provides better survival rates for those patients with just one station of metastatic mediastinal lymph nodes.
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BACKGROUND/AIMS: MicroRNAs (miRNAs) play important roles in tumorigenesis. We investigated the roles and mechanisms of miR-138 in human non-small cell lung cancer (NSCLC). METHODS: The expression of miR-138 was first examined in NSCLC cell lines and tumour tissues by real-time PCR The in vitro and in vivo functional effect of miR-138 was examined further. A luciferase reporter assay was conducted to confirm target association between miR-138 and the enhancer of zeste homolog 2 (EZH2). RESULTS: miR-138 was frequently downregulated in NSCLC cells and tissues. Overexpression of miR-138 inhibited proliferation of NSCLC cells in vitro and tumor growth in vivo. The EZH2 oncogene, which is often overexpressed in various human cancers and acts as an important regulator of cell growth and tumor invasion, was identified as a novel target of miR-138. miR-138 can bind to the 3' untranslated region (3' UTR) of EZH2 and suppress the expression of EZH2 at both mRNA and protein levels. Furthermore, knockdown of EZH2 phenocopied the tumor suppressive effects of miR-138 in cell models, whereas ectopic expression of EZH2 rescued the suppressive effects of miR-138. CONCLUSION: These findings define a tumor suppressor function for miR-138 in NSCLC and further suggest that miR-138 may represent a potential therapeutic target for NSCLC patients.
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MicroRNAs/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Regiões 3' não Traduzidas , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste , Pontos de Checagem da Fase G1 do Ciclo Celular , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Complexo Repressor Polycomb 2/genética , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Transplante HeterólogoRESUMO
BACKGROUND: This study was performed to assess early and late outcomes of pathologic N2 disease unexpectedly detected in patients with non-small cell lung cancer undergoing video-assisted thoracic surgery (VATS) lobectomy for clinical stage I. METHODS: We retrospectively reviewed the clinical features of patients with unexpected N2 non-small cell lung cancer and their early and late outcomes in the VATS lobectomy group versus the open thoracotomy lobectomy group. RESULTS: The overall survival time for all 358 patients was 33.26 ± 0.90 months. The overall survival time for 117 cases in the VATS lobectomy group was 36.02 ± 1.44 months. The overall survival time for 241 cases in the open thoracotomy lobectomy group was 31.92 ± 1.14 months. The survival rates for patients in the VATS lobectomy group were 92.31%, 36.75%, 5.13% at one, three, and five years, respectively. The survival rates for patients in the open thoracotomy lobectomy group were 92.12%, 21.58%, 2.49% at one, three, and five years, respectively. A significant difference was found between the two groups regarding this factor ( X Ì 2 = 3.88 , P = 0.049). CONCLUSIONS: VATS lobectomy is feasible and safe to perform on patients with minimal N2 non-small cell lung cancer. Even if lymph node metastasis is unexpectedly detected during surgery, with rigorous preoperative evaluation and systematic lymph node dissection, there is no need to convert to open thoracotomy lobectomy.
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Epithelial-to-mesenchymal transition (EMT) is a cellular process during which epithelial polarized cells become motile mesenchymal-appearing cells, which in turn promotes carcinoma invasion and metastasis. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural polyphenolic compound found in grapes, red wine and several other plants. Numerous reports in the literature indicate that resveratrol can suppress cancer invasion and metastasis. However, the underlying mechanisms of inhibiting metastasis by resveratrol are complex, not fully elucidated and the subject of intense scientific debate. Despite evidence indicating that EMT can be a target for resveratrol, little is known about the effect of resveratrol on lung cancer cells. Our previous studies demonstrated that TGF-ß1 induces EMT to promote lung adenocarcinoma invasion and metastasis. To understand the repressive role of resveratrol in lung cancer invasion and metastasis, we sought to investigate the potential use of resveratrol as an inhibitor of TGF-ß1-induced EMT development in A549 lung cancer cells in vitro. Here we show that when A549 cells are treated with TGF-ß1 and resveratrol, the latter inhibits the initiation of TGF-ß1-induced EMT. Our results show that 20 µM resveratrol increases expression of the epithelial phenotype marker E-cadherin and represses the expression of the mesenchymal phenotype markers, Fibronectin and Vimentin during the initiation of TGF-ß1-induced EMT. Resveratrol also inhibits expression of EMT-inducing transcription factors Snail1 and Slug, although the expression of the Twist1 transcription factor remained unchanged. Resveratrol inhibits the TGF-ß1-induced increase in cell adhesion, migration and invasion of A549 lung cancer cells. Taken together, our findings provide new evidence that resveratrol suppresses lung cancer invasion and metastasis in vitro through inhibiting TGF-ß1-induced EMT.
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Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Estilbenos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Caderinas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Fibronectinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Metástase Neoplásica , Resveratrol , Estilbenos/administração & dosagem , Fator de Crescimento Transformador beta1/farmacologia , Vimentina/genéticaRESUMO
BACKGROUND AND OBJECTIVE: In recent years, it has been proven that surgical treatment for solitary pulmonary metastases has achieved satisfactory results. Consequently, the study aims to investigate the diagnosis, indications for surgery, operative techniques, and prognostic factors of the surgical resection for solitary pulmonary metastases, and to improve the survival rate of patients with pulmonary metastases. METHODS: The medical records of 156 patients with surgical procedures at our institution were retrospectively reviewed. RESULTS: The primary tumors were verified as cancer in 134 cases, sarcoma in 21, and 1 contained unknown tissue. There was no perioperative mortality. A total of 153 patients returned for follow up. Follow-up time was 1 yr to 10 yr. The 5-year survival rates were 31.2%. The median survival time was 35.8 months. Systematic lymph node dissection was performed in 113 patients. The 5-year survival rates were 12.5% for lymph node-positive patients and 37.3% for lymph node-negative patients. The patients who underwent lobectomies had better survival rates, with a 5-year survival rate of 38.5%. CONCLUSIONS: Surgery is recommended for patients with solitary pulmonary metastasis if they fulfill the surgical indications and favorable outcomes can be achieved. VATS can be chosen for the patients. Hilar and mediastinal lymph node involvement and the surgical approach are potentially important prognostic factors.
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Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Adolescente , Adulto , Idoso , Criança , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Adulto JovemRESUMO
Metastasis of tumor cells is associated with epithelial-to-mesenchymal transition (EMT), which is a process whereby epithelial cells lose their polarity and acquire new features of mesenchyme. EMT has been reported to be induced by transforming growth factor-ß1 (TGF-ß1), but its mechanism remains elusive. In this study, we performed a study to investigate whether PI3K/Akt and MAPK/Erk1/2 signaling pathways involved in EMT in the human lung cancer A549 cells. The results showed that after treated with TGF-ß1 for 48 h, A549 cells displayed more fibroblast-like shape, lost epithelial marker E-cadherin and increased mesenchymal markers Vimentin and Fibronectin. Moreover, TGF-ß1-induced EMT after 48 h was accompanied by increased of cell migration and change of Akt and Erk1/2 phosphorylation. In addition, EMT was reversed by PI3K inhibitor LY294002 and MEK1/2 inhibitor U0126, which suggested that A549 cells under stimulation of TGF-ß1 undergo a switch into mesenchymal cells and PI3K/Akt and MAPK/Erk1/2 signaling pathways serve to regulate TGF-ß1-induced EMT of A549 cells.