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1.
Anticancer Res ; 39(11): 6231-6240, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704852

RESUMO

BACKGROUND/AIM: The present study aimed to prospectively examine the usefulness of interferon-gamma (IFN-γ) release (IGR) as a biomarker in non-small-cell lung cancer patients receiving immune checkpoint inhibitor treatment (ICI-Tx). PATIENTS AND METHODS: IGR was measured using enzyme-linked immunosorbent assay at four time points: within 14 days before ICI-Tx (T1), and 8±3 (T2), 22±7 (T3), and 43±7 (T4) days after ICI-Tx. RESULTS: Twenty-nine patients were divided into three groups based on IFN-γ levels in the IGR-positive control: Group-1 (n=8) with <10 IU/ml at T1, Group-2 (n=12) with a decrease in IFN-γ levels to <10 IU/ml at T3 and/or T4, and Group-3 (n=9) without changes in IFN-γ levels. Early progression and ICI-induced interstitial pneumonitis were frequently observed in Group-1 and Group-2, respectively. Group-3 exhibited more treatment cycles than the other groups. All three groups showed clear differences in clinical outcomes. CONCLUSION: IFN-γ levels could be a biomarker for ICI-Tx.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Interferon gama/metabolismo , Neoplasias Pulmonares/metabolismo , Linfócitos T/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Progressão da Doença , Feminino , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Interferon gama/sangue , Tuberculose Latente/diagnóstico , Tuberculose Latente/etiologia , Tuberculose Latente/metabolismo , Doenças Pulmonares Intersticiais/etiologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Estudos Prospectivos , Linfócitos T/imunologia , Fatores de Tempo
2.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704824

RESUMO

BACKGROUND/AIM: This study aimed to discuss the effect and possible molecular mechanisms of Aurora-A/NF-ĸB signaling on the radiotherapy resistance of human docetaxel-resistant lung adenocarcinoma cells. MATERIALS AND METHODS: The human lung adenocarcinoma SPC-A1 and SPC-A1/DTX cell lines were utilized in the present study. The MTT assay measured the sensitivity of cells to radiotherapy. The tumor-initiating ability of the cells was detected in vitro by cloning assays. Apoptosis was quantified by flow cytometry. Real-time quantitative PCR and western blotting were used to detect the mRNA and protein expression of the Aurora-A/NF-ĸB, respectively. Tumors transplanted subcutaneously into nude mice were used to test the effect of Aurora-A on the in vivo sensitivity of the tumors to radiotherapy. RESULTS: The SPC-A1/DTX docetaxel-resistant lung adenocarcinoma cells were radio-resistant compared with the parental SPC-A1 cells. Up-regulated aurora-A was responsible for the in vitro radio-resistance of docetaxel-resistant SPC-A1/DTX cells. Nuclear transcription factor NF-ĸB was identified as a downstream target gene of Aurora-A in SPC-A1/DTX cells, and NF-ĸB also participated in the radio-resistance of SPC-A1/DTX cells regulated by Aurora-A. CONCLUSION: The Aurora-A/NF-ĸB pathway is association with radio-resistance of human lung adenocarcinoma docetaxel-resistant cells.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Aurora Quinase A/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Neoplasias Pulmonares/metabolismo , NF-kappa B/metabolismo , Tolerância a Radiação , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/radioterapia , Animais , Antineoplásicos/farmacologia , Apoptose , Aurora Quinase A/genética , Proliferação de Células , Docetaxel/farmacologia , Resistência a Múltiplos Medicamentos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , NF-kappa B/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Anticancer Res ; 39(11): 6087-6095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704836

RESUMO

BACKGROUND: RAS GTPase-activating protein-binding protein (G3BP1) is an RNA-binding protein that is essential for assembling stress granules. Many functions related to the survival and progression of cancer have been reported. The current study aimed to investigate the role of G3BP1 in radio-sensitisation of cancer cells. MATERIALS AND METHODS: Radiation sensitivity and chemosensitivity were analysed in A549 and H460 cells transfected with G3BP1 siRNAs, and N-acetyl-L-cysteine (NAC) was used to elucidate the involvement of reactive oxygen species (ROS). RESULTS: G3BP1 depletion sensitised lung cancer cell lines to radiation, and the effect was related to ROS. G3BP1 depletion impaired the intracellular ROS scavenging system and NAC abolished the radiation-sensitive phenotypes caused by G3BP1 depletion. CONCLUSION: The study suggested G3BP1 as a promising target for radio- and chemosensitisation of lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Dano ao DNA/efeitos da radiação , DNA Helicases/antagonistas & inibidores , Neoplasias Pulmonares/radioterapia , Estresse Oxidativo/efeitos da radiação , Proteínas de Ligação a Poli-ADP-Ribose/antagonistas & inibidores , RNA Helicases/antagonistas & inibidores , Proteínas com Motivo de Reconhecimento de RNA/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , DNA Helicases/genética , DNA Helicases/metabolismo , Doxorrubicina/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/genética , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/genética , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 838-842, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750828

RESUMO

Objective To explore the preliminary application of metabonomics in the qualitative diagnosis of non-small cell lung cancer (NSCLC). Methods According to the pathological type, 201 patients with NSCLC were divided into squamous cell carcinoma (SCC) group (n=71) and adenocarcinoma (AC) group (n=130). Immunohistochemistry was used to detect the expression of ki67, cytokeratin 5/6 (CK5/6) and CK7. Ultra-high performance liquid chromatography-time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to detect serum metabolomics. Results SCC group showed typical SCC structure; ki67 proliferation index was 21.9%; CK5/6 expression was positive; CK7 expression was negative or weakly positive. The typical adenoid structure was found in the AC group; the proliferation index of ki67 was 17.6%; CK7 was positive; and CK5/6 was negative or weakly positive. UPLC-Q/TOF-MS screened 28 different metabolites, of which 6 were the most significant ones: L-leucine, carnitine, C16 sphinganine, 13, 16, 19-docosatrienoic acie (DA), LysoPE (18:2/0:0), PC (20:4/P-16:0). These metabolites had good diagnostic value, among which L-Leucine had the highest specificity and LysoPE had the highest sensitivity. Conclusion Metabolomic analysis of lung SCC and AC provides a new index for the differential diagnosis of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Metabolômica , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/metabolismo
5.
J Cancer Res Clin Oncol ; 145(12): 2937-2950, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620897

RESUMO

PURPOSE: Imaging biomarkers (IBMs) are increasingly investigated as prognostic indicators. IBMs might be capable of assisting treatment selection by providing useful insights into tumor-specific factors in a non-invasive manner. METHODS: We investigated six three-dimensional shape-based IBMs: eccentricities between (I) intermediate-major axis (Eimaj), (II) intermediate-minor axis (Eimin), (III) major-minor axis (Emj-mn) and volumetric index of (I) sphericity (VioS), (II) flattening (VioF), (III) elongating (VioE). Additionally, we investigated previously established two-dimensional shape IBMs: eccentricity (E), index of sphericity (IoS), and minor-to-major axis length (Mn_Mj). IBMs were compared in terms of their predictive performance for 5-year overall survival in two independent cohorts of patients with lung cancer. Cohort 1 received surgical excision, while cohort 2 received radiation therapy alone or chemo-radiation therapy. Univariate and multivariate survival analyses were performed. Correlations with clinical parameters were evaluated using analysis of variance. IBM reproducibility was assessed using concordance correlation coefficients (CCCs). RESULTS: E was associated with reduced survival in cohort 1 (hazard ratio [HR]: 0.664). Eimin and VioF were associated with reduced survival in cohort 2 (HR 1.477 and 1.701). VioS was associated with reduced survival in cohorts 1 and 2 (HR 1.758 and 1.472). Spherical tumors correlated with shorter survival durations than did irregular tumors (median survival difference: 1.21 and 0.35 years in cohorts 1 and 2, respectively). VioS was a significant predictor of survival in multivariate analyses of both cohorts. All IBMs showed good reproducibility (CCC ranged between 0.86-0.98). CONCLUSIONS: In both investigated cohorts, VioS successfully linked shape morphology to patient survival.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Idoso , Estudos de Coortes , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes
6.
Anticancer Res ; 39(10): 5297-5310, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570424

RESUMO

BACKGROUND/AIM: Low-molecular weight heparins (LMWHs) may possess putative antitumoral properties; however, the underlying mechanism(s) remains elusive. We evaluated the antiproliferative and antimigratory effects of enoxaparin (a LMWH) in lung adenocarcinoma A549 cells, and assessed the possible mechanism involved, and the effect on doxorubicin's efficacy. MATERIALS AND METHODS: Proliferation and migration were evaluated using BrdU and transwell assays, respectively. Immunoblotting was used to measure PAR-1, PAR-2, MMP-2, ERK1/2 and Akt proteins. Apoptosis and cell cycle studies examined the combined effect of enoxaparin and doxorubicin. RESULTS: Enoxaparin inhibited A549 cell proliferation and migration. Following PAR-1 gene knock down, enoxaparin's effect on A549 cell proliferation was diminished compared to scrambled siRNA. Our experiments verified that enoxaparin-mediated down-regulation of MAPK and PI3K, reduced MMP-2 expression and inhibited A549 cell migration. Additionally, enoxaparin increased doxorubicin's efficacy by enhancing apoptosis, while no effect on cell-cycle progression was observed. CONCLUSION: Results suggest that the anticancer activity of enoxaparin in A549 cells was mediated by the interference of two major PAR-1 downstream signaling pathways, MAPK/ERK and PI3K/Akt, which in turn inhibit proliferation and migration. Therefore, enoxaparin may be promising as an adjunct to traditional chemotherapy for lung cancer and warrants further investigation.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Enoxaparina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptor PAR-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células A549 , Adenocarcinoma de Pulmão/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Heparina de Baixo Peso Molecular/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo
7.
Anticancer Res ; 39(10): 5461-5471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570440

RESUMO

BACKGROUND/AIM: Multidrug resistance (MDR) is often associated with overexpression of P-glycoprotein (ABCB1) in cancer cells. Apatinib is a novel Vascular endothelial growth factor receptor-TKI (VEGFR-TKI) which inhibits the function of ABCB1 in certain cancers. This study aimed to investigate the effect of apatinib on the reversal of paclitaxel (PTX) resistance in A549 lung cancer cells (A549/PTX) and related mechanisms. MATERIALS AND METHODS: A549/PTX cells were treated with apatinib alone, PTX alone, or PTX and apatinib. Cell viability was measured by the CCK8 assay. Apoptosis rate, cell-cycle arrest, Rhodamine efflux and reactive oxygen species (ROS) generation were determined by flow cytometry. The intracellular paclitaxel concentration was measured by ultra performance liquid chromatography (UPLC). Protein levels were analyzed by western blotting. RESULTS: A549/PTX cells had significant resistance to PTX and higher expression of ABCB1 compared to A549 cells. Apatinib increased the cytotoxicity of PTX, enhanced PTX-induced apoptosis and cycle arrest, and triggered intracellular ROS generation in A549/PTX cells. In addition, apatinib treatment increased the concentration of intracellular PTX in A549/PTX cells. Apatinib-PTX combination inhibited AKT and ERK pathways. CONCLUSION: Apatinib reverses the drug resistance to PTX in A549 PTX-resistant cells through inhibiting the function of ABCB1 and resumes anti-cancer effects.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Piridinas/farmacologia , Células A549 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Zhonghua Zhong Liu Za Zhi ; 41(10): 742-747, 2019 Oct 23.
Artigo em Chinês | MEDLINE | ID: mdl-31648495

RESUMO

Objective: To investigate the effect of thymopoietin (TMPO) gene deleted by small interfering RNA (RNAi) on the proliferation and apoptosis of lung cancer cell A549 and its mechanism. Methods: TMPO siRNA was transfected into A549 cells by lipofection. The transfected siRNA control was used as a negative control, and the parent cells were used as blank control. Forty-eight hours later, the expression of TMPO in the transfected cells was detected by real-time fluorescent quantitative polymerase chain reaction (RT-PCR) and Western blot. Cell proliferation was detected by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay, cell cycle and apoptosis were detected by flow cytometry, the protein levels of proliferating cell nuclear antigen (PCNA), cleaved caspase-3, notch receptor 1 (Notch1) and mammalian rapamycin target protein (mTOR) were detected by Western blot analysis. Results: The results of RT-PCR and Western blot showed that the expression levels of TMPO mRNA in the blank control group, the negative control group and TMPO siRNA transfected group were (1.01±0.11), (0.99±0.10), (0.36±0.04), respectively, the protein levels were (0.27±0.02), (0.29±0.03), (0.08±0.10), respectively. The expression levels of TMPO mRNA and protein in the transfected group were significantly lower than those in the blank control and negative control group (P<0.05). The results of MTT assay showed that the OD values of the blank control group, the negative control group and the transfected group were (0.35±0.04), (0.37±0.04) and (0.34±0.03) at 24 h of transfection, respectively. The OD values at 48 h were (0.47±0.06), (0.46±0.08), (0.37±0.04), the OD values at 72 h were (0.75±0.08), (0.73±0.07), (0.49±0.05), respectively, and the OD values at 96 h were (1.09±0.07), (1.06±0.08), (0.56±0.06). The proliferation abilities of the transfected cells at 48, 72, 96 h were significantly lower than those of the blank control and the negative control group (P<0.05). The results of flow cytometry showed that the proportion of G(0)/G(1) phase cells in blank control group, negative control group and transfection group were (62.55±2.03)%, (61.24±3.15)%, (47.35±2.44)%, respectively. The proportion of cells in S phase were (17.12±1.31)%, (17.70±2.01)%, and (20.81±2.06)%, respectively. The proportion of cells in G(2)/M phase were (20.33±1.43)%, (21.06±1.52)%, (31.84±2.76)%, respectively. The proportion of cells in G(0)/G(1) phase of transfection group was significantly lower than those of blank control and negative control group (P<0.05). The proportion of cells in G(2)/M phase of transfection group was significantly higher than those of blank control and negative control group (P<0.05). The apoptosis ratio of the transfection group was (34.10±2.69)%, significantly higher than (2.96±0.03)% of the blank control and (3.01±0.04)% of the negative control group (P<0.05). Western blot analysis showed that PCNA, Notch1 and mTOR proteins were down-regulated while cleaved caspase-3 protein was up-regulated in A549 cells after deletion of TMPO. Conclusion: The inhibition of TMPO gene expression induced by small interfering RNA can significantly inhibit the proliferation and induce apoptosis of A549 cells, and the mechanism is associated with the inhibition of the activation of Notch1/mTOR signaling pathway.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Neoplasias Pulmonares/patologia , Timopoietinas/metabolismo , Animais , Apoptose/genética , Western Blotting , Linhagem Celular Tumoral , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Timopoietinas/genética , Transfecção
9.
Medicine (Baltimore) ; 98(43): e17559, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651857

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths among males and the second leading cause among females worldwide. Numerous studies have linked estrogen status to lung cancer outcome. However, there are studies with conflicting results about the effect of ERß on survival of lung cancer. The aim of this meta-analysis is to evaluate the prognostic impact of estrogen receptor beta expression on survival among NSCLC patients. METHODS: We will search 15 electronic databases, including PubMed, Web of Science, EMBASE, Cochrane Library, and CNKI from inception to June 1, 2019. We will include all cohort studies comparing overall survival of NSCLC patients with high or low estrogen receptor beta expression. The database searches will be supplemented by searching through citations and references. Two reviewers will independently screen search results to identify eligible articles, complete data collection, and conduct quality assessment. All disagreements will be resolved by an independent third reviewer. Methodological quality of the included studies will be assessed using the Newcastle- Ottawa scale. Discrepancies will be resolved by consensus or by consulting a third author. Meta-analyses will be performed, and findings will be reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the meta-analysis of observational studies in epidemiology (MOOSE) guidelines. RESULTS: The results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This review will provide a comprehensive evaluation of the evidence on the prognostic impact of ERß expression among NSCLC patients and will help clinicians find potential treatments based on estrogen signaling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Projetos de Pesquisa , Análise de Sobrevida , Revisão Sistemática como Assunto
10.
Chem Commun (Camb) ; 55(86): 12904-12907, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31584577

RESUMO

A novel type of hydrogen peroxide (H2O2)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H2O2-responsive behaviour of KA-NO-4 was thoroughly investigated. The NO-centered mechanism of action of KA-NO-4 was intracellularly studied.


Assuntos
Amidas/química , Antineoplásicos/química , Compostos Azo/química , Peróxido de Hidrogênio/química , Doadores de Óxido Nítrico/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Azo/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia
11.
J Cancer Res Clin Oncol ; 145(12): 2911-2920, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31646374

RESUMO

OBJECTIVE: To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer. METHODS: Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy. RESULTS: Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239-6.131; p = 0.013]. CONCLUSIONS: This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.


Assuntos
Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/metabolismo , Vimentina/metabolismo , Cromossomos Humanos Par 8/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos
12.
Curr Top Med Chem ; 19(23): 2128-2142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475900

RESUMO

KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Proteína Oncogênica p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Antineoplásicos/farmacologia , Quimioterapia Combinada , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo
13.
Gene ; 720: 144099, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31479715

RESUMO

Emerging evidence demonstrates that circular RNA (circRNA) is a novel class of non-coding RNA that plays a pivotal role in cancer. Recently, circ-PRMT5 was identified as an oncogene in bladder cancer. Nevertheless, its contribution to non-small cell lung cancer (NSCLC) is unknown. Herein, we aimed to clarify the biological role of circ-PRMT5 in NSCLC. High circ-PRMT5 expression was identified in NSCLC tissues and cell lines and positively correlated with larger tumor size, advanced clinic stage, lymph node metastasis as well as worse prognosis. Stable knockdown of circ-PRMT5 dramatically weakened the proliferative capacities of NSCLC cells both in vitro and in vivo. Mechanically, circ-PRMT5 could simultaneously effectively sponge three miRNAs (miR-377, miR-382 and miR-498) and alleviate their repression on the well-known oncogenic EZH2, resulting in increased EZH2 expression, thereby facilitating NSCLC progression. Importantly, a strong positive correlation between circ-PRMT5 and EZH2 expression was observed in NSCLC tissues. Overall, our data indicate that circ-PRMT5 is an oncogenic circRNA in NSCLC that can promote the growth of NSCLC via regulation of miR-377/382/498-EZH2 axis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , MicroRNAs/genética , Proteína-Arginina N-Metiltransferases/genética , RNA/genética , Animais , Apoptose , Biomarcadores Tumorais/análise , Carcinogênese , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proliferação de Células , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Life Sci ; 235: 116798, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31472149

RESUMO

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting ß-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy.


Assuntos
Apoptose , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica , Prognóstico , Proteínas Adaptadoras da Sinalização Shc/genética , Taxa de Sobrevida , Proteínas Wnt/genética , Via de Sinalização Wnt , beta Catenina/genética
15.
Chem Biol Interact ; 313: 108820, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518571

RESUMO

Natural products with potent activity and less toxicity provide major sources for development of novel anti-cancer drugs. Herein, we evaluated the effects and the underlying mechanisms of a novel piperlongumine (PL) analogue L50377 on non-small-cell lung cancer (NSCLC) cells. The results revealed that L50377 displayed greater potentials of suppressing cell growth than PL. In addition, L50377 promoted cell apoptosis and pyroptosis via stimulating reactive oxygen species (ROS) generation in NSCLC cells. More interestingly, ROS mediated NF-κB suppression might be implicated in the mechanisms of L50377-induced pyroptosis in NSCLC cells. Taken together, our results suggested that L50377 served as a novel chemical agent might have great potentials for NSCLC treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dioxolanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Dioxolanos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo
16.
Anticancer Res ; 39(9): 4637-4642, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519561

RESUMO

AIM: The aim of this study was to characterize the role of Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1 (AMMECR1) in human lung cancer cell lines. MATERIALS AND METHODS: AMMECR1 gene expression was evaluated in four lung cell lines, with A549 then selected for further in-depth examination. To characterize the role of AMMECR1, silencing was achieved utilizing lentivirus-mediated RNA interference, and confirmed by quantitative real-time polymerase chain reaction and western blotting. The impact of AMMECR1 silencing on cellular proliferation was assessed using Celigo-based and MTT assays. Apoptosis was determined using the annexin V-allophycocyanin single staining method. Cell-cycle arrest was assessed by flow cytometry. Finally, colony formation was assessed using Giemsa staining. RESULTS: In A549 cells, AMMECR1 silencing was found to significantly suppress cell proliferation, reduce colony formation, promote apoptosis, and arrest cells in the S and G2/M phases. CONCLUSION: AMMECR1 plays a critical role in cell proliferation, cell-cycle progression, and apoptosis of human lung cancer cells, and may serve as a potential therapeutic target for non-small-cell lung cancer.


Assuntos
Apoptose/genética , Ciclo Celular/genética , Neoplasias Pulmonares/genética , Proteínas/genética , Células A549 , Linhagem Celular Tumoral , Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas/metabolismo , RNA Mensageiro/genética
17.
J Cancer Res Clin Oncol ; 145(12): 3055-3065, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31522278

RESUMO

PURPOSE: Combined immunotherapy with anti-programmed cell death-ligand 1 (PD-L1) and an inhibitor of cluster of differentiation 47 (CD47) have exhibited preliminary anti-tumor effect. Our study attempted to describe the PD-L1/CD47 expression status in pulmonary sarcomatoid carcinoma (PSC), and explore its survival impact and relevance with cytotoxic T lymphocytes and macrophages infiltration. METHODS: 148 patients with PSC who underwent surgeries were retrospectively reviewed. Tissue microarrays were conducted for immunohistochemistry (IHC) of PD-L1, CD47, CD8 and CD68. RESULTS: 54 (36.5%) and 78 (52.7%) cases were positive for PD-L1 and CD47, respectively, and 36 (24.3%) of them demonstrated PD-L1/CD47 co-expression. There was a significant correlation between PD-L1 and CD47 expression (P = 0.011). The median overall survival (OS) was 22.5 months (range 0.9-102.4 months). The univariate analysis demonstrated a significantly worse OS in cases with CD47 expression (hazard ratio [HR], 1.66; 95% CI, 1.14-2.42, P = 0.008) and PD-L1/CD47 co-expression (HR, 1.75; 95% CI, 1.15-2.67, P = 0.009). The multivariate analysis demonstrated PD-L1/CD47 co-expression (HR, 1.83; 95% CI, 1.17-2.87, P = 0.008), T stage, M stage, completeness of resection and adjuvant therapy were independent prognostic factors for OS. There was a significant relevance between PD-L1 expression and PD-L1/CD47 co-expression with higher densities of CD8-positive T lymphocytes (P = 0.004, 0.012, respectively) and CD68-positive macrophages (P = 0.026, 0.034, respectively). CONCLUSION: We demonstrated the PD-L1/CD47 co-expression status in PSC. PD-L1 expression correlated with CD47 expression, and PD-L1/CD47 co-expression correlated with poorer prognosis and may serve as a predictive biomarker for combined dual-targeting immunotherapy in PSC patients.


Assuntos
Antígeno B7-H1/metabolismo , Antígeno CD47/metabolismo , Carcinoma/metabolismo , Neoplasias Pulmonares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Carcinoma/patologia , Diferenciação Celular/fisiologia , Feminino , Humanos , Imunoterapia/métodos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Estudos Retrospectivos , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/patologia
18.
J Cancer Res Clin Oncol ; 145(10): 2495-2506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31494736

RESUMO

PURPOSE: Histology samples are important for the appropriate administration of tumor type-specific cytotoxic and molecular-targeted therapies for the treatment of non-small cell lung cancer (NSCLC). When biopsy samples lack a definite morphology, a diagnosis can be selected from three subtypes based on immunohistochemistry (IHC) results, as follows: favor adenocarcinoma (ADC), favor squamous cell carcinoma (SQC), or not otherwise specified (NOS)-null. In terms of patient outcome, however, the validity of IHC-based classifications remains unknown. METHODS: A large series of 152 patients with advanced NSCLC whose diagnoses had been made based on morphological findings and who had been homogeneously treated were enrolled. We used IHC staining (TTF-1, SP-A, p40, and CK5/6) to examine tumor samples and refined the diagnoses. We then analyzed the pathological subgroups according to the IHC staining results. RESULTS: IHC profiling resulted in 50% of the cases being classified as favor ADC, 31% being classified as favor SQC, and 19% being classified as NOS-null groups. Compared with the favor ADC and favor SQC groups, the NOS-null group had a significantly poorer outcome. Pemetrexed-containing platinum regimens produced a response rate similar to that of other platinum doublet regimens in the favor ADC group (44% vs. 46%), whereas it produced a poorer response in the favor SQC group (0% vs. 52%) and the NOS-null group (0% vs. 24%). The favor ADC group tended to have a higher percentage of EGFR positivity and ALK positivity than the favor SQC group (25% vs. 11% and 7% vs. 0%, respectively). CONCLUSIONS: These findings support the use of immunohistological subtyping of NSCLC biopsy specimens to select patient-appropriate treatments.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Resultado do Tratamento , Adulto Jovem
19.
Cancer Sci ; 110(11): 3595-3602, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31512325

RESUMO

Coxsackievirus and adenovirus receptor (CAR) is a single-pass transmembrane protein that is associated with adenoviral infection. CAR is involved in the formation of epithelial tight junctions and promotes tumor growth in some cancers. Previously, we developed mouse monoclonal antibodies against human CAR and found that one, mu6G10A, significantly inhibited tumor growth in xenografts of human cancer cells. Herein, we generated and characterized a mouse-human chimeric anti-CAR antibody (ch6G10A) from mu6G10A. ch6G10A had binding activity, inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in vivo anti-tumor activity against CAR-expressing prostate cancer DU-145 cells. In addition, cancer tissue array analysis confirmed that CAR is highly expressed in neuroendocrine lung cancers including small cell lung cancer, and treatment with ch6G10A effectively inhibited in vivo subcutaneous tumor growth of NCI-H69 small cell lung cancer cells in nude mice. Moreover, treatment with mu6G10A effectively inhibited both in vivo orthotopic tumor growth and distant metastatic formation in mouse xenograft models of a highly metastatic subline of human small cell lung cancer DMS273 cells. These results suggest that targeting therapy to CAR with a therapeutic antibody might be effective against several cancer types including small cell lung cancer.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/antagonistas & inibidores , Neoplasias Pulmonares/terapia , Neoplasias da Próstata/terapia , Carcinoma de Pequenas Células do Pulmão/terapia , Animais , Citotoxicidade Celular Dependente de Anticorpos , Proteínas do Sistema Complemento/imunologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/imunologia , Proteína de Membrana Semelhante a Receptor de Coxsackie e Adenovirus/metabolismo , Neoplasias das Glândulas Endócrinas/metabolismo , Neoplasias das Glândulas Endócrinas/terapia , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias da Próstata/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 619-624, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537247

RESUMO

Objective To investigate the effects of Astragalus polysaccharide (APS) on autophagy and expression of microtubule-associated protein 1 light chain 3B (LC3B), mammalian target of rapamycin (mTOR) and beclin1 in xanthine oxidase (XOD)-induced autophagic model of non-small cell lung cancer A549 cells. Methods A549 cells were divided into five groups: control group, model group, 100, 200 and 400 µg/mL APS-treated group. Except for control group, all groups were administered XOD for 24 hours to establish autophagic models. Morphology of autophagosome was detected by transmission electron microscopy (TEM) and the number was counted by monodansylcadaverine (MDC) staining. The expression levels of LC3B, beclin1 and mTOR were detected by Western blot analysis. Results Compared with the control group, the number of autophagosome in the model group increased; the expression of LC3B and beclin1 significantly increased; while the expression of mTOR significantly decreased. Compared with the model group, the number of autophagosome decreased remarkably; the expression of LC3B and beclin1 severely decreased, and the expression of mTOR obviously increased in 200 or 400 µg/mL APS-treated group. Conclusion APS reduces the level of autophagy, down-regulates the expression of LC3B and beclin1, and increases mTOR expression in the autophagic model of A549 cells induced by XOD.


Assuntos
Astrágalo (Planta)/química , Autofagia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Polissacarídeos/farmacologia , Células A549 , Proteínas Relacionadas à Autofagia , Proteína Beclina-1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Xantina Oxidase
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