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1.
Toxicol Lett ; 320: 37-45, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31778776

RESUMEN

As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 µM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.


Asunto(s)
Benzo(a)pireno/toxicidad , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , ARN Largo no Codificante/metabolismo , Células A549 , Antígenos CD/genética , Antígenos CD/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Invasividad Neoplásica , ARN Largo no Codificante/genética , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Factores de Tiempo , Regulación hacia Arriba
2.
Life Sci ; 241: 117134, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31811854

RESUMEN

AIMS: Non-small cell lung cancer (NSCLC), characterized by extensive metastasis and poor prognosis, is the most common type of lung cancer. Dysregulation of certain lncRNAs is known to be linked to the tumorigenesis of NSCLC. However, the specific roles in NSCLC for many other lncRNAs, such as linc01088, remain largely unknown. MATERIALS AND METHODS: The expression patterns of linc01088, p21 and EZH2 were examined both in NSCLC tissues and cell lines using RT-qPCR assay. CCK-8, colony formation, immunofluorescence staining, and flow cytometry assays were employed to evaluate the effects of linc01088 on NSCLC cell proliferation properties. RNA immunoprecipitation (RIP) assay was performed to determine the direct binding relationship between linc01088 and zeste homolog 2 (EZH2). Western blot and RT-qPCR analysis were performed to assess p21 level within knockdown of either linc01088 or EZH2. Nude mouse subcutaneous NSCLC models were constructed for further validating the effects and mechanisms of linc01088 in vivo. KEY FINDINGS: linc01088 and EZH2 were highly expressed both in NSCLC tissues and cell lines. Knockdown of linc01088 suppressed the proliferation of NSCLC cells, and prolonged the G1 phase while shortened S and G2-M phases. RIP assay revealed the direct binding relationship between linc01088 and EZH2. Knockdown of either linc01088 or EZH2 induced up-regulation of p21 expression, which subsequently inhibited the tumor growth. SIGNIFICANCE: We demonstrated that linc01088 could promote cell proliferation via binding with EZH2 to repress p21, which aggravates the tumorigenesis of NSCLC. Therefore, linc01088 might be a potential oncogene and target for novel anti-tumor therapies.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , ARN Largo no Codificante/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
3.
J Cancer Res Clin Oncol ; 146(1): 273-285, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31641854

RESUMEN

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). METHODS: We extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed. RESULTS: The AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664-5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543-4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04). CONCLUSIONS: Our results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Transducción de Señal
4.
Cancer Sci ; 111(1): 186-199, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31746077

RESUMEN

Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3ß/ß-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/genética , Ácido Láctico/metabolismo , Estrés Oxidativo/genética , Transactivadores/genética , Transcripción Genética/genética , Activación Transcripcional/genética , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3 beta/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Especies Reactivas de Oxígeno/metabolismo
5.
Acta Cytol ; 64(1-2): 16-29, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-30878997

RESUMEN

Pulmonary cytology is a challenging diagnostic tool, and it is usually evaluated considering medical history and radiological findings in order to reach an accurate diagnosis. Since the majority of lung cancer patients have an advanced stage at diagnosis, a cytological specimen is frequently the only material available for diagnosis and further prognostic/predictive marker determination. Several types of specimens can be obtained from the respiratory system (including sputum, bronchoalveolar lavage, bronchial brushing, fine needle aspiration, and pleural fluid) with different technical preclinical management protocols and different diagnostic yields. Immunocytochemistry (ICC) has a pivotal role in the determination of diagnostic, prognostic, and predictive markers. Therefore, limited cytology samples are to be used with a cell-sparing approach, to allow both diagnostic ICC evaluation as well as predictive marker assessment by ICC or specific molecular assays. In this review, we describe the most common ICC markers used for the diagnosis and prognostic/predictive characterization of thoracic tumors in different cytological specimens.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Citodiagnóstico/métodos , Inmunohistoquímica/métodos , Neoplasias Pulmonares/metabolismo , Pulmón/metabolismo , Biopsia con Aguja Fina/métodos , Lavado Broncoalveolar/métodos , Broncoscopía/métodos , Humanos , Pulmón/patología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Esputo/metabolismo
6.
Cancer Sci ; 111(1): 200-208, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31778288

RESUMEN

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11ß1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non-small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT-PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cadenas alfa de Integrinas/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad
7.
Life Sci ; 241: 117165, 2020 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-31838136

RESUMEN

AIMS: Previous work has reported the closely correlation between inflammation and carcinogenesis, while the role of NALP3, the key component of inflammasome activation in NSCLC remains elusive. This study was to unravel the mechanism of NALP3 on modulating NSCLC cancer cell growth. METHODS: IHC and immuno-blot were performed to analyze expression of NALP3 and indicated molecules. CCK-8 and xenograft nude mice assay were used to evaluate cell growth in vitro and in vivo. Bioenergetics assay was performed to measure OXPHOS and aerobic glycolysis. siRNA and shRNA were constructed to knockdown endogenous NALP3 and DNMT1. Co-immunoprecipitation was applied to confirm the interaction between NALP3 and DMAP1. BioProfile FLEX analyzer and Lactate Reagent Kit were used to measure relative level glucose uptake and lactate production. KEY FINDINGS: We reported NALP3 were up-regulated in NSCLC tumor tissues. NALP3 depletion suppressed cancer cell growth in vitro and in vivo. Moreover, data showed depletion of NALP3 promoted cell bioenergetics switch from aerobic glycolysis to OXPHOS. Additionally, we found NALP3 interacted with DMAP1 and alteration of NALP3 increased DNMT1 level. Subsequently, we clarified depletion of DNMT1 significantly suppressed NSCLC cell growth and orchestrated cellular metabolism which was similar to the effects of NALP3 knockdown. Finally, our data showed high NALP3 was associated with poor outcomes, and correlated with TNM stage and differentiation. SIGNIFICANCE: Current study elucidated NALP3 could promote metabolic reprogramming to regulate NSCLC cell growth and suggested that NALP3 may be considered as a novel biomarker and therapeutic target for NSCLC patients.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/secundario , Metabolismo Energético , Regulación Neoplásica de la Expresión Génica , Glucólisis , Neoplasias Pulmonares/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proliferación Celular , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
8.
J Cancer Res Clin Oncol ; 146(2): 457-466, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31853661

RESUMEN

PURPOSE: Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75 years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1. METHODS: A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded. RESULTS: Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88) years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0 months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS. CONCLUSIONS: Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Neoplasias Pulmonares/metabolismo , Masculino , Supervivencia sin Progresión , Resultado del Tratamiento
9.
Recent Results Cancer Res ; 215: 105-125, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605226

RESUMEN

Circulating tumour cells (CTCs) constitute a potential tumour surrogate that could serve as "liquid biopsy" with the advantage to be a minimally invasive approach compared to traditional tissue biopsies. As CTCs are thought to be the source of metastatic lesions, their analysis represents a potential means of tracking cancer cells from the primary tumour en route to distant sites, thus providing valuable insights into the metastatic process. However, several problems, such as their rarity in the peripheral blood, the technical limitations of single-cell downstream analysis and their phenotypic variability, make CTC detection and molecular characterisation very challenging. Nevertheless, in the last decade, there has been an exponential increase of interest in the development of powerful cellular and molecular methodologies applied to CTCs. In this chapter, we focus on the recent advances of functional studies and molecular profiling of CTCs. We will also highlight the clinical relevance of CTC detection and enumeration, and discuss their potential as tumour biomarkers with special focus on lung cancer.


Asunto(s)
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/análisis , Humanos , Células Neoplásicas Circulantes/patología
10.
Pol J Pathol ; 70(3): 183-188, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31820861

RESUMEN

CD63 has been suggested to participate in tumorigenesis, invasion, and metastasis. In this study, we aimed to investigate the prognostic significance of CD63 expression in non-small cell lung cancer (NSCLC). CD63 expression was evaluated in 133 cases of NSCLC via immunohistochemical staining using tissue microarray blocks. We assessed the relationship between CD63 expression and clinicopathological characteristics, as well as the prognostic significance of CD63 expression in NSCLC. CD63 expression was significantly correlated with patient gender (p < 0.001), smoking history (p = 0.020), histologic type (p < 0.001), tumour stage (p = 0.016), lymph node metastasis (p = 0.034), and TNM stage (p = 0.007). A multivariate Cox proportional hazards regression analysis determined low CD63 expression to be an independent factor for unfavourable disease-free survival (DFS) (HR = 2.043, 95% CI: 1.035-4.035, p = 0.040), and Kaplan-Meier analysis indicated that the low CD63 expression group showed significantly lower DFS than the high CD63 expression group of patients with NSCLC (p = 0.019). Low CD63 expression might be an unfavourable prognostic factor in patients with NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Tetraspanina 30/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales
11.
Pol J Pathol ; 70(3): 189-197, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31820862

RESUMEN

Large tumor suppressor kinase 2 (LATS2) is a core component in the Hippo signaling pathway, and it functions as a tumor suppressor associated with tumor cell proliferation and apoptosis. The purpose of this study is to explore LATS2 expression and its clinicopathological significance in non-small cell lung cancer (NSCLC). We examined LATS2 protein expression by immunohistochemistry in 184 resected NSCLC specimens using tissue microarrays. Low LATS2 expression was significantly related to disease recurrence (p = 0.047). In survival analysis, the low LATS2 expression group showed a statistically poorer overall survival (OS) (p = 0.004) and disease-free survival (DFS) (p = 0.014) than the high expression group. In multivariate analysis, downregulated LATS2 expression in NSCLC could be an independent prognostic factor of poor OS and DFS. Furthermore, we evaluated the prognostic significance of LATS2 expression in two major NSCLC subtypes, squamous cell carcinoma and adenocarcinoma. The low LATS2 expression group showed worse prognosis than the high LATS2 expression group (OS [p = 0.144] and DFS [p = 0.022] in squamous cell carcinoma and OS [p = 0.045] and DFS [p = 0.271] in adenocarcinoma). We demonstrated that downregulated LATS2 expression may predict aggressive biologic behavior and a worse prognosis in NSCLC and we also suggested the possibility of LATS2 as a therapeutic target in both squamous cell carcinoma and adenocarcinoma.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Pronóstico
12.
Pol J Pathol ; 70(3): 198-204, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31820863

RESUMEN

Agrin has recently been identified as a novel oncogene that is overexpressed in several types of human cancers. However, its role in lung cancer has not yet been investigated. The purpose of the current study was to investigate agrin protein expression in lung cancer and evaluate its clinicopathological and prognostic significance. In this study, A total of 86 lung adenocarcinoma samples paired with adjacent non-tumour tissue samples and eight lung adenocarcinoma non-paired samples were selected for immunohistochemical staining for agrin. Strong staining of agrin in nuclei of lung adenocarcinoma tissues was observed, but not in the nuclei of normal lung tissues (p < 0.001). Consistent with staining in lung adenocarcinoma tissues, the nuclei staining of agrin was also detected in lung cancer cell lines by immunofluorescence. This is the first report demonstrating that agrin is highly expressed in nuclei of lung adenocarcinoma tissues and that it is strongly correlated with lymph node metastasis (p = 0.002), clinical stage (p = 0.024), and poor differentiation (p = 0.022). Agrin-positive nuclear staining of lung adenocarcinoma cells could be used to identify greatly increased risk of metastasis in patients after surgery, which might serve as a valuable prognostic marker.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Agrina/metabolismo , Neoplasias Pulmonares/metabolismo , Biomarcadores de Tumor/metabolismo , Humanos , Metástasis Linfática , Estadificación de Neoplasias , Pronóstico
13.
Anticancer Res ; 39(12): 6585-6593, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810924

RESUMEN

BACKGROUND/AIM: Human lung adenocarcinoma PC14 cells without mutations in the epidermal growth factor receptor (EGFR) are less sensitive to gefitinib than PC9 cells with EGFR mutations. We report the involvement of tetrandrine in autophagy flux as a mechanism that enhances the sensitivity of PC14 cells to gefitinib. MATERIALS AND METHODS: Sensitivity to gefitinib was determined by a growth inhibition assay, and quantitative real-time PCR, western blotting, and fluorescent immunostaining were used to detect autophagy. RESULTS: In PC14 cells, combined treatment with gefitinib and tetrandrine caused a significant increase in gefitinib sensitivity and autophagy-related mRNAs and proteins (LC3, etc.), and the LC3 protein accumulated in lysosomes. Furthermore, an autophagy flux assay revealed that tetrandrine inhibited lysosomes and that gefitinib promoted autophagy. Finally, the sensitivity of PC14 cells to gefitinib was enhanced with chloroquine. CONCLUSION: Tetrandrine possibly increases the susceptibility of PC14 cells to gefitinib by lysosomal inhibition.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Bencilisoquinolinas/farmacología , Gefitinib/farmacología , Neoplasias Pulmonares/metabolismo , Lisosomas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Autofagia , Bencilisoquinolinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Gefitinib/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Lisosomas/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/genética
14.
Anticancer Res ; 39(12): 6621-6633, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810927

RESUMEN

BACKGROUND/AIM: The antidepressant duloxetine is known as a serotonin-norepinephrine reuptake inhibitor, used for treating depression and anxiety. TRAIL selectively induces cell death in a variety of tumor cells by binding to its membrane death receptor (DR). The aim of the study was to examine whether duloxetine affects TRAIL-mediated apoptosis. MATERIALS AND METHODS: Cell viability and apoptosis was measured by morphological image, crystal violet staining, MTT and LDH assay. Immunocytochemistry and western blotting techniques were applied to detect autophagy and apoptosis indicator proteins. TEM assay was used to determine the autophagy. RESULTS: Duloxetine treatment considerably sensitizes human lung adenocarcinoma cells to TRAIL-mediated apoptosis by targeting TRAIL-DR5. Treatment with duloxetine inhibited AMPK phosphorylation and resulted in increased p62 and microtubule-associated protein 1A/1B light chain 3B-II levels, indicating inhibition of autophagy flux. Blockade of DR5 with DR5-specific small-interfering RNA negatively regulated the apoptotic effect. CONCLUSION: Clinical administration of TRAIL in combination with duloxetine may serve as a therapeutic approach for the treatment of TRAIL-resistant lung cancer cells.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis/efectos de los fármacos , Clorhidrato de Duloxetina/farmacología , Neoplasias Pulmonares , Inhibidores de Captación de Serotonina y Norepinefrina/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño , Proteínas de Unión al ARN/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Regulación hacia Arriba
15.
Eur J Histochem ; 63(4)2019 Dec 11.
Artículo en Inglés | MEDLINE | ID: mdl-31833327

RESUMEN

Serine-arginine protein kinase (SRPK) belongs to a class of cell cycle regulating kinases that can phosphorylate proteins containing serine/arginine-Rich (SR) regions. SR proteins are a family of RNA binding phosphoproteins that control both constitutive and alternative pre-mRNA splicing events. However, little is known about their role in non-small cell lung cancer (NSCLC). In the present study, we found that serine-arginine protein kinase 2 (SRPK2) expression was upregulated in NSCLC tissues compared with adjacent normal tissues. Kaplan-Meier curve analyses showed that the overall survival time of NSCLC patients with high SRPK2 expression was shorter than those with low SRPK2 expression. Overexpression of SRPK2 promoted NSCLC cell proliferation and cell cycle arrest, while knockdown of SRPK2 inhibited proliferation and promoted cell cycle arrest in NSCLC cell lines. SRPK2 promoted the transcriptional regulation of E2F1 on downstream cell cycle related genes through phosphorylation of SC35. Xenograft model showed that SRPK2 promoted tumor growth in vivo. SRPK2 phosphorylated SC35 and phosphorylated SC35 activated E2F1 transcription of cyclin-related proteins, thereby promoting the cycle progression of NSCLC. Our findings demonstrated that SRPK2 may be a potential therapeutic target for NSCLC clinical therapy, which plays an important role in the progression of NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Puntos de Control del Ciclo Celular/fisiología , Regulación hacia Abajo/fisiología , Factor de Transcripción E2F1/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Anticuerpos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología
16.
Anticancer Res ; 39(12): 6723-6730, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810937

RESUMEN

BACKGROUND/AIM: Phosphoserine aminotransferase 1 (PSAT1) is an enzyme implicated in serine biosynthesis, and its overexpression has been linked to cancer cell proliferation. Therefore, targeting PSAT1 is considered to be an anticancer strategy. MATERIALS AND METHODS: The viability of non-small cell lung cancer (NSCLC) cells was measured by MTT assay. Protein and mRNA expression were determined by western blot and reverse transcription polymerase chain reaction, respectively. RESULTS: Glutamine-limiting conditions were generated through glutamine deprivation or CB-839 treatment, which induced PSAT1 expression in NSCLC cells. PSAT1 expression induced by glutamine-limiting conditions was regulated by activating transcription factor 4. Knock-down of PSAT1 enhanced the sensitivity of NSCLC cells to glutamine-limiting conditions. Interestingly, ionizing radiation induced PSAT1 expression, and knocking down PSAT1 increased cell sensitivity to ionizing radiation. CONCLUSION: Inhibiting PSAT1 might aid in the treatment of lung cancer, and PSAT1 may be a therapeutic target for lung cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Glutamina/metabolismo , Neoplasias Pulmonares/metabolismo , Transaminasas/metabolismo , Factor de Transcripción Activador 4/metabolismo , Bencenoacetamidas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Línea Celular Tumoral , Supervivencia Celular , Técnicas de Sustitución del Gen , Glutaminasa/antagonistas & inhibidores , Glutamina/antagonistas & inhibidores , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , ARN Mensajero/metabolismo , Tolerancia a Radiación , Tiadiazoles/farmacología , Transaminasas/genética
17.
Anticancer Res ; 39(12): 6851-6857, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31810952

RESUMEN

BACKGROUND: This study aimed to determine whether the neutrophil-to-lymphocyte ratio (NLR) reflected poor treatment benefits in patients with tumor proportion score (TPS) ≥50% and who under went first-line pembrolizumab monotherapy. PATIENTS AND METHODS: This study retrospectively analyzed patients with untreated stage III/IV or recurrent non-small cell lung cancer (NSCLC) with TPS ≥50% and who received pembrolizumab monotherapy at two hospitals between February 2017 and April 2019. The NLR was calculated from pre-treatment complete blood counts. RESULTS: A total of 51 previously untreated patients with NSCLC who had TPS ≥50% and who underwent pembrolizumab monotherapy were evaluated. Multivariate analysis revealed that high NLR, Eastern Cooperative Oncology Group performance status (PS) ≥2, stage IV or recurrent cancer, and TPS=50-74% were significantly and independently associated with poor progression-free survival. Moreover, high NLR and PS ≥2 were significantly associated with short overall survival. CONCLUSION: A high pre-treatment NLR was associated with significantly short progression-free and overall survival in previously untreated patients with NSCLC with high expression of programmed cell-death ligand 1 treated with pembrolizumab monotherapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Femenino , Humanos , Recuento de Leucocitos , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Regulación hacia Arriba
18.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1023-1029, 2019 Nov.
Artículo en Chino | MEDLINE | ID: mdl-31878999

RESUMEN

Objective To explore the expression of vascular endothelial growth factor receptor 3 (VEGFR3) and its significance in lung adenocarcinoma and to examine the effect of VEGFR3 knockdown on the biological behaviors of A549 cells. Methods Immunohistochemistry was used to detect the expression of VEGFR3 in 78 pieces of lung adenocarcinoma tissue and 35 of paracancerous tissue. Relationships between VEGFR3 and clinicopathological indices were also analyzed. Correlations between lung adenocarcinoma patient survival and the expression of vascular endothelial growth factor-C (VEGF-C) or VEGFR3 were analyzed using the TCGA database. VEGFR3 expression was knocked down in A549 cells using RNA interference, and cell proliferation was assessed using a CCK-8 assay. Cell migration and invasion were detected using TranswellTM assays. The effect of siRNA-mediated knockdown of EGFR3 in A549 cells on AKT pathway activity was assessed by Western blot analysis. Results Expression of VEGFR3 was significantly higher in the lung adenocarcinoma tissue than in the adjacent tissue, and positively correlated with TNM stage and lymph node metastasis. The survival rate of patients with high VEGFR3 expression was significantly lower than that of patients with low VEGFR3 expression. Exogenous VEGF-C promoted the expression of VEGFR3, and activated the AKT signaling pathway. Silencing of VEGFR3 inhibited the proliferation, migration, and invasiveness of A549 cells, and reduced the activation of the AKT signaling pathway by VEGF-C. Conclusion High expression of VEGFR3 in the lung adenocarcinoma tissue is positively correlated with poor prognosis. Silencing VEGFR3 can block AKT pathway activity and inhibit the proliferation, migration, and invasion of A549 cells.


Asunto(s)
Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/patología , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Células A549 , Adenocarcinoma del Pulmón/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Invasividad Neoplásica , Pronóstico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor C de Crecimiento Endotelial Vascular/metabolismo
19.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 838-842, 2019 Sep.
Artículo en Chino | MEDLINE | ID: mdl-31750828

RESUMEN

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.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Metabolómica , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/metabolismo
20.
Anticancer Res ; 39(11): 5991-5998, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31704824

RESUMEN

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.


Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , Aurora Quinasa A/metabolismo , Resistencia a Antineoplásicos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias Pulmonares/metabolismo , FN-kappa B/metabolismo , Tolerancia a Radiación , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/radioterapia , Animales , Antineoplásicos/farmacología , Apoptosis , Aurora Quinasa A/genética , Proliferación Celular , Docetaxel/farmacología , Resistencia a Múltiples Medicamentos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/radioterapia , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , FN-kappa B/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
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