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1.
Magy Onkol ; 65(2): 103-111, 2021 Jun 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081758

RESUMO

The therapeutic impact of KRAS mutations remains controversial in bone metastatic lung adenocarcinoma (LADC). Therefore, our aim was to investigate the effects of KRAS mutational status on overall survival (OS) in these patients according to bisphosphonate therapy (BTx) and radiation therapy (RTx). In total, 134 LADC patients diagnosed with simultaneous bone metastasis were included in this study. The results of the univariate (p=0.008) and multivariate (p=0.004) survival analyses indicated that KRAS mutation is a negative prognostic factor. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS wild-type tumors. Importantly, the concomitant use of BTx and RTx might increase the OS irrespective of KRAS status compared to BTx or RTx alone. In summary, our results might contribute to the development of new therapeutic approaches with regards to KRAS mutational status in bone metastatic LADC.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Colorretais , Neoplasias Pulmonares , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Difosfonatos/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genética
2.
Biomed Res Int ; 2021: 8817898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997043

RESUMO

Background: Genomic testing gives guidance to the treatment options in lung adenocarcinoma patients, but some patients are unable to obtain tissue samples due to lesion location or intolerance. Cell-free circulating tumor DNA (ctDNA) tested in plasma or pleural effusion is an advanced access to solve the problem. Our study descriptively identified the genetic variations of advanced Chinese lung adenocarcinoma patients and analyzed the overall survival of patients with EGFR mutations. Methods: A total of 152 patients' plasma samples were included, and gene mutations were detected by NGS using an Illumina Miseq tabletop sequencer. Results: Frequencies of altered were EGFR 46.05%, ALK 7.24%, KRAS 6.58%, PIK3CA 6.58%, PTEN 2.63%, HER2 1.97%, MET 1.97%, BRAF 1.32%, NF1 1.32%, and ROS1 0.66%. We identified 48 cases with double or triple driver gene mutations. Multiple mutations were more frequently observed in EGFR and PIK3CA genes. Patients harboring coexistent mutations with an EGFR mutation tended to have a shorter overall survival than those with exclusively EGFR mutations. Conclusion: EGFR, ALK, and KRAS were common driver gene in Chinese patients with stage IV lung adenocarcinoma. Multiple mutations were detected in the ctDNA samples and involve more EGFR and PIK3CA mutations. The existence of coexisting gene mutations may have adverse effects on the prognosis of patients with EGFR mutation. The unknown mutations discovered by NGS may provide new targets for gene targeting therapy, and ctDNA test by NGS is an effective method for making appropriate treatment choices.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma de Pulmão/sangue , Biomarcadores Tumorais/genética , China , DNA Tumoral Circulante/sangue , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade
3.
Nat Commun ; 12(1): 2722, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976164

RESUMO

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.


Assuntos
Adenocarcinoma in Situ/genética , Adenocarcinoma de Pulmão/genética , Carcinogênese/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Lesões Pré-Cancerosas/genética , Transcriptoma , Adenocarcinoma in Situ/imunologia , Adenocarcinoma in Situ/patologia , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Carcinogênese/imunologia , Carcinogênese/patologia , Aberrações Cromossômicas , Células Clonais , Variações do Número de Cópias de DNA , Metilação de DNA , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Inata , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Proteínas de Neoplasias/imunologia , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Transdução de Sinais , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
4.
Med Sci Monit ; 27: e929333, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33979320

RESUMO

BACKGROUND Lung adenocarcinoma (LUAD) is a type of non-small cell carcinoma. Its pathogenesis is being explored and there is no cure for the disease. MATERIAL AND METHODS The Gene Expression Omnibus (GEO) was searched to obtain data on expression of messenger RNA. GEO2R, an interactive web tool, was used to calculate the differentially expressed genes (DEGs) in LUAD. All the DEGs from different datasets were imported into VENNY 2.1 (https://bioinfogp.cnb.csic.es/tools/venny/index.html) to identify the intersection of the DEGs. An online analysis tool, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), was used to help understand the biological meaning of DEG enrichment in LUAD. Cytoscape 3.7.2 was used to perform centrality analysis and visualize hub genes and related networks. Furthermore, the prognostic value of the hub genes was evaluated with the Kaplan-Meier plotter survival analysis tool. RESULTS The GEO database was used to obtain RNA sequencing information for LUAD and normal tissue from the GSE118370, GSE136043, and GSE140797 datasets. A total of 376 DEGs were identified from GSE118370, 248 were identified from GSE136403, and 718 DEGs were identified from GSE140797. The 10 genes with the highest degrees of expression - the hub genes - were CAV1, TEK, SLIT2, RHOJ, DGSX, HLF, MEIS1, PTPRD, FOXF1, and ADRB2. In addition, Kaplan-Meier survival evaluation showed that CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 were associated with favorable outcomes for LUAD. CONCLUSIONS CAV1, TEK, SLIT2, HLF, MEIS1, PTPRD, FOXF1, and ADRB2 are hub genes in the DEG interaction network for LUAD and are involved in the development of and prognosis for the disease. The mechanisms underlying these genes should be the subject of further studies.


Assuntos
Adenocarcinoma de Pulmão/genética , Fatores de Transcrição de Zíper de Leucina Básica/genética , Regulação Neoplásica da Expressão Gênica/genética , Expressão Gênica/genética , Neoplasias Pulmonares/genética , Células A549 , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , Neoplasias Pulmonares/patologia , Prognóstico , Mapas de Interação de Proteínas , Análise de Sobrevida
5.
Gene ; 790: 145689, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33964375

RESUMO

OBJECTIVE: GALNT2/14 are members of the glycosyltransferase protein family, which initiate mucin-type O-glycosylation of peptides in the Golgi apparatus. However, the correlation between GALNT2/14 and disease prognosis and methylation in lung adenocarcinoma (LUAD) remains unclear. Thus, we sought to identify their potential values in LUAD. METHODS: GALNT2/14 expressions were analyzed using publicly-available datasets. The association between GALNT2/14 and disease prognosis was evaluated. In addition, gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to explore the potential biological functions of GALNT2/14. The correlation between the copy number variations and methylation level of GALNT2/14 and their mRNA expressions was analyzed via cBioPortal. Finally, we explored the prognostic value of the GALNT2/14 methylation levels by MethSurv in LUAD. RESULTS: GALNT2/14 were highly expressed in LUAD tumor tissue than normal tissue (P < 0.001). Multivariate analysis showed that high GALNT2/14 expressions were both an independent prognostic factor. GSEA found that GALNT2/14 expressions were associated with the methylation, gene silencing, and cell division, whereas immune analysis showed that GALNT2/14 expressions positively correlated with the expression level of PD-L1. Finally, the methylation levels of GALNT2/14 negatively correlated with the GALNT2/14 expressions (R = -0.26 and -0.36, P < 0.001, respectively), and patients with GALNT2/14 hypomethylation had worse overall survival than patients with high methylation (P < 0.05). CONCLUSIONS: This study demonstrated that the overexpression of GALNT2/14 in LUAD can serve as biomarkers for poor prognosis. The biological functions of GALNT2/14 are potentially related to methylation, gene silencing, tumorigenesis, and cell division. These findings help elucidate the role of GALNT2/14 in tumorigenesis and provide additional insight for therapy and prognosis of LUAD.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , N-Acetilgalactosaminiltransferases/genética , Adenocarcinoma de Pulmão/genética , Variações do Número de Cópias de DNA , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Prognóstico , Taxa de Sobrevida
6.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(3): 329-335, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33849822

RESUMO

OBJECTIVE: To investigate the role and expression pattern of LIM-domain binding protein 2 (LDB2) in lung adenocarcinoma. OBJECTIVE: We studied the expression pattern of LDB2 in lung adenocarcinoma based on data from the online databases TCGA, GEO and CPTAC, and the results were verified in lung adenocarcinoma tissues and cells using immunohistochemistry, qRT-PCR and Western blotting. The relationship between LDB2 and the prognosis of patients with lung adenocarcinoma was analyzed using GEPIA and GEO databases. We further analyzed the role of LDB2 in regulating cell behaviors in a H1299 cell model over-expressing LDB2 using cell counting, soft agar colony forming assay and flow cytometry. The m6A binding sites on LDB2 were confirmed by bioinformatics analysis and MeRIP-qPCR assays. The effect of YTHDC2 on LDB2 was examined using qRT-PCR and Western blotting, and the binding of YTHDC2 to the transcript of LDB2 was verified with RIP-qPCR assays. Dual luciferase reporter assay was performed to verify YTHDC2 functioning via m6A sites. OBJECTIVE: LDB2 expression was significantly decreased in lung adenocarcinoma in comparison with normal tissues based on data from TCGA, GEPIA and CPTAC, and the same results were obtained from 80 lung adenocarcinoma tissues and 17 adjacent normal tissues. Similarly, LDB2 expression was decreased in lung adenocarcinoma cells as compared with 16HBE cells. The data from Prognoscan and GEPIA suggested that a high LDB2 expression was positively correlated with a more favorable outcome of lung adenocarcinoma patients. LDB2-overexpressing H1299 cells showed a significant inhibition of proliferative activity with cell cycle arrest in S phage. Bioinformatics analysis and MeRIP-qPCR assay confirmed the presence of m6A sites on LDB2. The m6A reader YTHDC2 was positively related with LDB2 in lung adenocarcinoma based on data from GEPIA (r=0.22). Overexpression YTHDC2 significantly enhanced LDB2 expression in H1299 cells by about 19.35 folds. Dual luciferase reporter assay showed that YTHDC2 enhanced the promoter activity in the wild-type group but not in deletion group. OBJECTIVE: LDB2 expression can be up-regulated by m6A reader YTHDC2 in lung adenocarcinoma to inhibit the proliferation of the tumor cells in vitro.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Proteínas de Transporte , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas com Domínio LIM , Neoplasias Pulmonares/genética , RNA Helicases , Fatores de Transcrição/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-33799753

RESUMO

The aim of the current study is to investigate potential associations among Long Noncoding RNA (LncRNA) H19 single nucleotide polymorphism (SNP) and epidermal growth factor receptor (EGFR) phenotypes on the clinicopathological characteristics of lung adenocarcinoma (LADC). Five loci of LncRNA H19 SNPs (rs217727, rs2107425, rs2839698, rs3024270, and rs3741219) were genotyped by using TaqMan allelic discrimination in 223 LADC patients with wild-type EGFR phenotype and 323 LADC individuals with EGFR mutations. After the statistical analyses, patients with the EGFR mutation were related to a higher distribution frequency of rs217727 SNP CT heterozygote (p = 0.030), and the female population with EGFR mutation demonstrated a higher distribution frequency of rs217727 SNP CT heterozygote (p < 0.001) and rs2107425 CT heterozygote (p = 0.002). In addition, the presence of LncRNA H19 SNP rs217727 T allele (CT + TT) in patients with EGFR wild-type was associated to higher tumor T status (stage III or IV, p = 0.037) and poorer cell differentiation status (poor differentiation, p = 0.012) compared to those EGFR wild-type individuals with LncRNA H19 SNP rs217727 CC allele. Besides, a prominently higher tumor T status was found in subjects with LncRNA H19 SNP rs2107425 T allele (CT + TT) (stage III or IV, p = 0.007) compared to EGFR wild-type LADC individuals with LncRNA CC allele in EGFR wild-type patients. Our findings suggest that the presence of LncRNA H19 SNP rs217727 is related to the EGFR mutation in LADC patients, and the LncRNA H19 SNP rs217727 and rs2107425 are associated with progressed tumor status for LADC patients with EGFR wild-type.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , RNA Longo não Codificante , Adenocarcinoma de Pulmão/genética , Estudos de Casos e Controles , Receptores ErbB/genética , Feminino , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética
8.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924522

RESUMO

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.


Assuntos
RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Neoplasias Pulmonares/genética , Mucina-1/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Longo não Codificante/metabolismo , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Modelos Biológicos , Inibidores de Proteínas Quinases/uso terapêutico , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos
9.
Cancer Invest ; 39(5): 409-422, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33813994

RESUMO

BASP1 is involved in signal transduction and cytoskeleton formation and plays a tumor-promoting or tumor-suppressing role in cancers. We found BASP1 was overexpressed in lung adenocarcinoma tissues and promoted the proliferation and migration of lung adenocarcinoma cells. The mechanism may be related to inhibition of cell apoptosis and abnormal activation of the Wnt/ß-catenin pathway and epithelial-mesenchymal transformation. BASP1 is associated with poor prognosis in lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/genética , Biologia Computacional/métodos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/metabolismo , Progressão da Doença , Humanos , Prognóstico , Transfecção
10.
J Int Med Res ; 49(4): 3000605211004021, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33794676

RESUMO

OBJECTIVE: This study aimed to identify a predictive marker of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant advanced lung adenocarcinoma. METHODS: A cohort of 190 patients with EGFR-mutant advanced lung adenocarcinoma was analyzed. Receiver operating characteristic curve analysis was used to evaluate the optimal cutoffs for fibrinogen levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) for predicting progression-free survival (PFS). Univariate and multivariate survival analyses were performed to identify factors correlated with PFS and overall survival (OS). RESULTS: High NLR was associated with worse performance status. In univariate analysis, fibrinogen levels, NLR, and PLR were correlated with OS and PFS. In multivariate analysis, all three variables remained predictive of OS, whereas only fibrinogen levels and PLR were independent prognostic factors for PFS. Furthermore, the combination of fibrinogen levels and PLR (F-PLR score) could stratify patients into three groups with significantly different prognoses, and the score was independently predictive of survival. CONCLUSION: The F-PLR score predicted the prognosis of patients with EGFR-mutant advanced lung adenocarcinoma who received EGFR-TKIs, and this score may serve as a convenient blood-based marker for identifying high-risk patients.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Receptores ErbB/genética , Fibrinogênio , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Linfócitos , Neutrófilos , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
11.
J Pak Med Assoc ; 71(2(A)): 531-536, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33819244

RESUMO

OBJECTIVE: To analyse clinical and molecular features in patients with surgically resected patients with lung cancer harbouring anaplastic lymphoma kinase fusion. METHODS: The retrospective study was conducted at Zhejiang Cancer Hospital, Hangzhou, China, and comprised data from November 2013 to August 2015 of lung cancer patients. Anaplastic lymphoma kinase, epidermal growth factor receptor, kirsten rat sarcoma viral oncogene, v-raf murine sarcoma viral oncogene homolog, REarranged during Transfection proto-oncogene, c-ros oncogene 1 receptor kinase, V-Erb-B2 avian erythroblastic leukaemia viral oncogene homolog 2 and mesenchymal epithelial transition factor were noted using next generation sequencing. Clinicopathological parameters were also investigated. All patients were followed up till August 10, 2017. Data was analysed using SPSS 22. RESULTS: Of the 19 patients, 15(79%) were non-smokers. Anaplastic lymphoma kinase rearrangements occurred in the acinar predominant in 6(31.6%), solid predominant 6(31.6%) and mucinous predominant 4(21%) adenocarcinomas. There was 1(5.2%) patient with epidermal growth factor receptor 21 G863D mutation. The 3-year disease-free survival rate in 5(26.3%) cases of anaplastic lymphoma kinase variant 1 was 5(100%), while in the 14(73.7%) cases of non-variant 1 group it was 9(64.3%) (p=0.257). CONCLUSIONS: Anaplastic lymphoma kinase rearrangements did not tend to be accompanied with other driver genes. Difference between variant 1 and non-variant 1 patients was uncertain and needs to be further investigated.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/cirurgia , Quinase do Linfoma Anaplásico/genética , Animais , China , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Camundongos , Mutação , Proteínas Proto-Oncogênicas/genética , Ratos , Receptores Proteína Tirosina Quinases/genética , Estudos Retrospectivos
12.
Eur J Radiol ; 139: 109710, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33862316

RESUMO

PURPOSE: To develop and validate a CT-based radiomic model to simultaneously diagnose anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutation status of lung adenocarcinoma and to assess whether peritumoural radiomic features add value in the prediction of mutation status. METHODS: 503 patients with pathologically proven lung adenocarcinoma containing information on the mutation status were retrospectively included. Intratumoural and peritumoural radiomic features of the primary lesion were extracted from CT. We proposed two-level stepwise binary radiomics-based classification models to diagnose ALK (step1) and EGFR mutation status (step2). The performance of proposed models and added value of peritumoural radiomic features were evaluated by using the areas under receiver operating characteristic curves (AUC) and Obuchowski index in the development and validation sets. RESULTS: Regarding the prediction of ALK rearrangement, the diagnostic performance of the intratumoural radiomic model showed the AUC of 0.77 and 0.68 for the development and validation sets, respectively. As for EGFR mutation, the diagnostic performance of the intratumoural radiomic model showed the AUCs of 0.64 and 0.62 for the development and validation sets, respectively. The radiomics added value to the model based on clinical features (development set [radiomics + clinical model vs. clinical model]: Obuchowski index, 0.76 vs. 0.66, p < 0.001; validation set: 0.69 vs. 0.61, p = 0.075). Adding peritumoural features resulted in no improvement in terms of model performance. CONCLUSION: The CT radiomics-based model allowed the simultaneous prediction of the presence of ALK and EGFR mutations while adding value to the clinical features.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/genética , Quinase do Linfoma Anaplásico/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Mutação , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
13.
J Transl Med ; 19(1): 161, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879171

RESUMO

BACKGROUND: Lung cancer is one of the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still cannot be effectively treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and its potential mechanism and explored the possibility of targeting DKC1 for LUAD therapy. METHODS: The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases were used to examine the DKC1 transcript levels. Gene expression with clinical information from tissue microarray of LUAD were analyzed for associations between DKC1 expression and LUAD prognosis. In addition, loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo. RESULTS: DKC1 is overexpressed in LUAD compared with adjacent normal tissues. High expression of DKC1 predicts the poor overall survival. DKC1 knockdown in LUAD cell lines induced G1 phase arrest and inhibited cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. In addition, the abundance of DKC1 is positively correlated with telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) levels in LUAD. DKC1 downregulation resulted in decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis. CONCLUSIONS: Our results show that high DKC1 expression indicates poor prognosis of LUAD and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Apoptose/genética , Proteínas de Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Proteínas Nucleares , Telômero/genética
14.
BMJ Case Rep ; 14(4)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906872

RESUMO

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Carbazóis , Feminino , Humanos , Lactamas Macrocíclicas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Músculo Esquelético , Proteínas de Fusão Oncogênica/genética , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico
15.
Jpn J Clin Oncol ; 51(6): 956-965, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33829270

RESUMO

OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Compostos de Anilina/farmacologia , Neoplasias Pulmonares/genética , Receptor IGF Tipo 1/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia
16.
Biomed Res Int ; 2021: 6628682, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33860045

RESUMO

Background: Human Schlafen 5 (SLFN5) is reported to inhibit or promote the proliferation of several specific types of cancer cells by our lab and other researchers. We are curious about its implications in lung adenocarcinoma (LUAC), a malignant tumor with a high incidence rate and high mortality. Method: Lentiviral stable transfections of SLFN5-specific shRNA for knockdown and SLFN5 full-length coding sequence for overexpression were performed in LUAC cell for proliferation analysis in vitro and in vivo in nude mice. Clinical LUAC samples were collected for immunohistochemical analysis of SLFN5 protein levels. Results: We found that knockdown of endogenous SLFN5 upregulates cancer cell proliferation while inhibiting apoptosis. Besides, SLFN5 inhibition on proliferation was also observed in a nude mouse xenograft model. In contrast, overexpression of exogenous SLFN5 inhibited cell proliferation in vitro and in vivo and promoted apoptosis. As to the signaling pathway, we found phosphatase and tensin homolog on chromosome 10 (PTEN) was positively regulated by SLFN5, while its downstream signaling pathway AKT/mammalian target of rapamycin (mTOR) was inhibited. Moreover, compared with adjacent normal tissues, SLFN5 protein levels were markedly decreased in lung adenocarcinoma tissues. In conclusion, these suggest that human SLFN5 plays inhibitory roles in LUAC progression through the PTEN/PI3K/AKT/mTOR pathway, providing a potential target for developing drugs for lung cancer therapy in the future.


Assuntos
Adenocarcinoma de Pulmão/patologia , Apoptose , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células A549 , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Animais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Camundongos Nus , Fosforilação , Transdução de Sinais , Transcrição Genética
17.
Medicine (Baltimore) ; 100(16): e25246, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33879658

RESUMO

ABSTRACT: Lung adenocarcinoma (LUAD) is a lethal malignancy worldwide and a major public health concern. We explored the potential clinical significance for LUAD of ATP-binding cassette (ABC), sub-family C, consisting of ABCC1-6, 8-12, and cystic fibrosis transmembrane conductance regulator (CFTR).Five hundred LUAD patients from The Cancer Genome Atlas database were used for analysis, including differential expression and diagnostic and prognostic significance. Oncomine and MERAV databases were used to validate differential expression and diagnostic significance. A risk score model was constructed using prognosis-related ABCC members. Prognosis-related genes were further explored to correlate their expression with tumor stage progression. Interaction networks, including biological processes and metabolic pathways, were constructed using Cytoscape software and STRING website.ABCC1-3 consistently showed high expression in tumor tissues (all P ≤ 0.05). Most datasets indicated that ABCC5, 10, and 11 were highly expressed in tumor tissues whereas ABCC6, 9, and CFTR were highly expressed in nontumor tissues (all P ≤ 0.05). Diagnostic significance of ABCC3 and ABCC5 was consistently assessed and validated in three datasets (all area under the curve > 0.700) whereas ABCC6, 8, 10, 11, and CFTR were assessed in The Cancer Genome Atlas dataset and validated in one dataset (all area under the curve > 0.700). Prognostic analysis indicated that ABCC2, 6, and 8 mRNA expression was associated with survival of LUAD (all adjusted P ≤ .037). The risk score model constructed using ABCC2, 6, and 8 suggested prognostic significance for survival predictions. ABCC2 expression was associated with tumor stage, whereas ABCC6 and 8 were not. Interaction networks indicated that they were involved in establishment of localization, ion transport, plasma membrane, apical plasma membrane, adenylyl nucleotide binding, ABC transporters, ABC transporter disorders, ABC-family-protein-mediated transport, and bile secretion.Differentially expressed ABCC2 and ABCC5 might be diagnostic whereas ABCC2, 6, and 8 may be prognostic biomarkers for LUAD, possibly through ABC-family-mediated transporter disorders.


Assuntos
Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Idoso , Biomarcadores Tumorais/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Bases de Dados Genéticas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Análise de Sobrevida
18.
Braz J Med Biol Res ; 54(5): e9700, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33825780

RESUMO

Lung adenocarcinomas are usually sensitive to radiation therapy, but some develop resistance. Radiation resistance can lead to poor patient prognosis. Studies have shown that lung adenocarcinoma cells (H1299 cells) can develop radioresistance through epithelial-mesenchymal transition (EMT), and this process is regulated by miRNAs. However, it is unclear which miRNAs are involved in the process of EMT. In our present study, we found that miR-183 expression was increased in a radioresistant lung adenocarcinoma cell line (H1299R cells). We then explored the regulatory mechanism of miR-183 and found that it may be involved in the regulation of zinc finger E-box-binding homeobox 1 (ZEB1) expression and mediate EMT in lung adenocarcinoma cells. qPCR results showed that miR-183, ZEB1, and vimentin were highly expressed in H1299R cells, whereas no difference was observed in E-cadherin expression. Western blot results showed that ZEB1 and vimentin were highly expressed in H1299R cells, while E-cadherin expression was decreased. When miR-183 expression was inhibited in H1299R cells, radiation resistance, proliferation, and cell migration were decreased. The expression of ZEB1 and vimentin in H1299R cells was decreased, while the expression of E-cadherin was increased. Moreover, miR-183 overexpression in H1299 cells enhanced radiation resistance, proliferative capacity, and cell migration ability. The expression of ZEB1 and vimentin in H1299 cells was increased, while that of E-cadherin was decreased. In conclusion, miR-183 may promote EMT and radioresistance in H1299 cells, and targeting the miR-183-ZEB1 signaling pathway may be a promising approach for lung cancer treatment.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/radioterapia , Linhagem Celular Tumoral , Movimento Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , MicroRNAs/genética
19.
Life Sci ; 276: 119439, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785338

RESUMO

AIMS: Our study aimed to investigate the function of GALNT2 in lung adenocarcinoma (LUAD). MAIN METHODS: We used network tools and tissue microarray immunohistochemistry to measure the expression levels of GALNT2 in LUAD. Kaplan-Meier curves and Cox regression methods were used in survival analysis. We detected the role of GALNT2 in cell lines by Cell Counting Kit-8, colony formation, transwell, and wound healing assays. We performed Western blotting to evaluate downstream protein levels. KEY FINDINGS: GALNT2 was highly expressed in LUAD samples and indicated a poor prognosis. Knockdown of GALNT2 suppressed cell line proliferation, migration, and invasion abilities, while overexpression of GALNT2 enhanced those phenotypes. Moreover, GALNT2 activated Notch/Hes1-PTEN-PI3K/Akt signaling axis. SIGNIFICANCE: Our data confirmed the cancer-promoting effect of GALNT2, and might provide a new approach for LUAD therapy.


Assuntos
Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/patologia , N-Acetilgalactosaminiltransferases/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Idoso , Apoptose , Biomarcadores Tumorais/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , N-Acetilgalactosaminiltransferases/genética , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Taxa de Sobrevida , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Células Tumorais Cultivadas
20.
Medicine (Baltimore) ; 100(8): e24917, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33663128

RESUMO

RATIONALE: Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance. PATIENT CONCERNS: A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again. DIAGNOSIS: The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma. INTERVENTIONS: Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again. OUTCOMES: Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient's resistance to lorlatinib. LESSONS: We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Ósseas/secundário , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Quinase do Linfoma Anaplásico/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Proteínas de Ciclo Celular , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Evolução Fatal , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Proteínas Associadas aos Microtúbulos , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Serina Endopeptidases
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