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BACKGROUND: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. METHODS: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. RESULTS: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. CONCLUSION: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis.
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Anticolesterolemiantes , Autofagia , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Ezetimiba , Fibrosis Pulmonar Idiopática , Ezetimiba/uso terapéutico , Ezetimiba/farmacología , Animales , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Humanos , Ratones , Autofagia/efectos de los fármacos , Masculino , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/farmacología , Femenino , Ratones Transgénicos , Bleomicina , Pulmón/patología , Pulmón/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Ratones Endogámicos C57BL , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Colesterol/metabolismoRESUMEN
BACKGROUND: We aimed to investigate the role of angiopoietin (Angpt) as a predictive biomarker for sepsis by evaluating associations between plasma Angpt and various inflammatory cytokines and mortality in critically ill patients with sepsis. METHODS: This study was a retrospective cohort study of the prospectively collected samples and clinical data of 145 patients with sepsis who were admitted to the medical intensive care unit (ICU) of a 2000-bed university tertiary referral hospital in South Korea. We collected plasma within 24 h of medical ICU admission, and several biomarkers (Angpt-1 and -2, Tie2, vascular endothelial growth factor, interleukin (IL)-1ß, IL-10, IL-18, IL-6, interferon gamma-induced protein-10, and tumor necrosis factor-α) were measured using a Human Magnetic Luminex Screening Assay kit. RESULTS: Plasma Angpt-2 was correlated with IL-6 (rs = 0.555) and tumor necrosis factor-α (rs = 0.559). Plasma Angpt-2 (rs = 0.530) and Angpt-2/1 (rs = 0.562) were correlated with the Sequential Organ Failure Assessment (SOFA) score. The area under the curve (AUC) for the 28-day mortality prediction for the plasma Angpt-2/1 ratio was 0.736; AUCs for the Acute Physiology and Chronic Health Evaluation II (APACHE II) and SOFA scores were 0.659 and 0.745, respectively. Using multivariate Cox proportional hazard regression analysis for 28-day mortality, we found that acute respiratory distress syndrome (hazard ratio (HR) = 2.235, 95% CI = 1.163-4.296,p = 0.016), APACHE II score (HR = 1.127, 95% CI = 1.037-1.224,p = 0.005), and Angpt-2/1 > 3.2 (HR = 2.522, 95% CI = 1.205-5.278,p = 0.014) were risk factors for 28-day mortality. CONCLUSIONS: Plasma Angpt-2 was related to cytokines, but Angpt-2/1 ratio was a good predictor of 28-day mortality in patients with sepsis.
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Angiopoyetina 1/sangre , Angiopoyetina 2/sangre , Biomarcadores/sangre , Plasma/metabolismo , Sepsis/sangre , Anciano , Enfermedad Crítica , Citocinas/sangre , Femenino , Humanos , Inflamación/sangre , Inflamación/patología , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Pronóstico , República de Corea , Síndrome de Dificultad Respiratoria/sangre , Estudios Retrospectivos , Sepsis/patologíaRESUMEN
Insulin-like growth factor-1 (IGF-1) levels are known to increase in the bronchoalveolar lavage fluid (BALF) of patients with acute respiratory distress syndrome. Herein, we investigated the role of IGF-1 in lipopolysaccharide (LPS)-induced lung injury. In LPS-treated cells, expressions of receptor-interacting protein 3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) were decreased in IGF-1 receptor small interfering RNA (siRNA)-treated cells compared to control cells. The levels of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, IL-10, tumour necrosis factor-α, and macrophage inflammatory protein 2/C-X-C motif chemokine ligand 2 in the supernatant were significantly reduced in IGF-1 receptor siRNA-treated cells compared to control cells. In LPS-induced murine lung injury model, total cell counts, polymorphonuclear leukocytes counts, and pro-inflammatory cytokine levels in the BALF were significantly lower and histologically detected lung injury was less common in the group treated with IGF-1 receptor monoclonal antibody compared to the non-treated group. On western blotting, RIP3 and phosphorylated MLKL expressions were relatively decreased in the IGF-1 receptor monoclonal antibody group compared to the non-treated group. IGF-1 may be associated with RIP3-mediated necroptosis in vitro, while blocking of the IGF-1 pathway may reduce LPS-induced lung injuries in vivo.
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Lesión Pulmonar/prevención & control , Necrosis/etiología , Receptor IGF Tipo 1/farmacología , Animales , Antígenos CD/metabolismo , Apoptosis/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Cadherinas/metabolismo , Lipopolisacáridos , Pulmón/metabolismo , Lesión Pulmonar/inducido químicamente , Macrófagos/metabolismo , Ratones , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/fisiología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
BACKGROUND: The development of chemo-resistance in non-small lung cancer is a major obstacle in treating patients. Hypoxia is a commonly faced microenvironment in solid tumor and suggested to be related to both autophagy and chemo-resistance. METHODS: In this study, we investigated the role of hypoxia-induced autophagy in acquiring chemo-resistance in both cancer cell (A549) and human cancer tissue RESULTS: Hypoxic exposure (1 % O2) of A549 cell stimulated autophagic induction in cancer cells, shown by increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 in Western blot, increased GFP-LC puncta in confocal microscopy, and increased number of double-membrane autophagic vacuoles in electron micrographs. Hypoxic exposure also induced resistance of cancer cells to cisplatin, and LC3B siRNA restored the sensitivity of cancer cells to chemotherapy. Furthermore, Human lung cancer tissues that experienced chemotherapy showed increase of LC3BI to LC3BII conversion and decrease of p62/sequestosome1 compared with chemo-naïve cancer tissue in Western blot. CONCLUSION: Autophagy may play an important role in acquiring resistance to chemotherapy in lung cancer and hypoxia related pathway seems to be involved in autophagy induction.
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Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos , Neoplasias Pulmonares/tratamiento farmacológico , Microambiente Tumoral , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/ultraestructura , Hipoxia de la Célula , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/ultraestructura , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Interferencia de ARN , Proteína Sequestosoma-1 , Factores de Tiempo , TransfecciónRESUMEN
Genome-wide association studies (GWAS) identified over fifty loci associated with lung cancer risk. However, the genetic mechanisms and target genes underlying these loci are largely unknown, as most risk-associated-variants might regulate gene expression in a context-specific manner. Here, we generated a barcode-shared transcriptome and chromatin accessibility map of 117,911 human lung cells from age/sex-matched ever- and never-smokers to profile context-specific gene regulation. Accessible chromatin peak detection identified cell-type-specific candidate cis-regulatory elements (cCREs) from each lung cell type. Colocalization of lung cancer candidate causal variants (CCVs) with these cCREs prioritized the variants for 68% of the GWAS loci, a subset of which was also supported by transcription factor abundance and footprinting. cCRE colocalization and single-cell based trait relevance score nominated epithelial and immune cells as the main cell groups contributing to lung cancer susceptibility. Notably, cCREs of rare proliferating epithelial cell types, such as AT2-proliferating (0.13%) and basal cells (1.8%), overlapped with CCVs, including those in TERT. A multi-level cCRE-gene linking system identified candidate susceptibility genes from 57% of lung cancer loci, including those not detected in tissue- or cell-line-based approaches. cCRE-gene linkage uncovered that adjacent genes expressed in different cell types are correlated with distinct subsets of coinherited CCVs, including JAML and MPZL3 at the 11q23.3 locus. Our data revealed the cell types and contexts where the lung cancer susceptibility genes are functional.
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Dysfunction of mitochondrial metabolism is implicated in cellular injury and cell death. While mitochondrial dysfunction is associated with lung injury by lung inflammation, the mechanism by which the impairment of mitochondrial ATP synthesis regulates necroptosis during acute lung injury (ALI) by lung inflammation is unclear. Here, we showed that the impairment of mitochondrial ATP synthesis induces receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis during lung injury by lung inflammation. We found that the impairment of mitochondrial ATP synthesis by oligomycin, an inhibitor of ATP synthase, resulted in increased lung injury and RIPK3 levels in lung tissues during lung inflammation by LPS in mice. The elevated RIPK3 and RIPK3 phosphorylation levels by oligomycin resulted in high mixed lineage kinase domain-like (MLKL) phosphorylation, the terminal molecule in necroptotic cell death pathway, in lung epithelial cells during lung inflammation. Moreover, the levels of protein in bronchoalveolar lavage fluid (BALF) were increased by the activation of necroptosis via oligomycin during lung inflammation. Furthermore, the levels of ATP5A, a catalytic subunit of the mitochondrial ATP synthase complex for ATP synthesis, were reduced in lung epithelial cells of lung tissues from patients with acute respiratory distress syndrome (ARDS), the most severe form of ALI. The levels of RIPK3, RIPK3 phosphorylation and MLKL phosphorylation were elevated in lung epithelial cells in patients with ARDS. Our results suggest that the impairment of mitochondrial ATP synthesis induces RIPK3-dependent necroptosis in lung epithelial cells during lung injury by lung inflammation.
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OBJECTIVES: Related innate immune system activation and diagnostic factors of sepsis are not fully understood. The aim of this study was to analyze the clinical value of full-length tryptophanyl-tRNA synthetase (WRS) induced through inflammatory stimuli for the detection of sepsis and prediction of mortality in critically ill patients. METHODS: This was a retrospective analysis of blood samples collected prospectively from patients in the medical intensive care unit (ICU) at Yonsei University College of Medicine, from March 2015 to June 2018. The ability of WRS to detect sepsis and predict mortality were compared to those of procalcitonin (PCT), C-reactive protein (CRP), and interleukin 6 (IL-6), and with Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. RESULTS: A total of 241 study patients were enrolled, of whom 190 (78.8%) had been diagnosed with sepsis on ICU admission. The areas under the receiver operating characteristics curves (AUROCs) for sepsis discrimination with WRS, PCT, CRP, and IL-6 levels, and SOFA and APACHE II scores were 0.864, 0.727, 0.625, 0.651, 0.840, and 0.754, respectively. The prediction of 28-day mortality in patients with sepsis using WRS levels was possible and non-inferior to that with the SOFA score. CONCLUSIONS: WRS secreted early in sepsis may be useful not only for the early detection of sepsis, but also for the prediction of mortality in critically ill patients.
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Sepsis/diagnóstico , Triptófano-ARNt Ligasa/sangre , APACHE , Anciano , Proteína C-Reactiva/metabolismo , Enfermedad Crítica , Femenino , Hospitalización , Humanos , Unidades de Cuidados Intensivos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Puntuaciones en la Disfunción de Órganos , Polipéptido alfa Relacionado con Calcitonina/sangre , Pronóstico , Estudios Retrospectivos , Sepsis/sangre , Sepsis/enzimología , Triptófano-ARNt Ligasa/genética , UniversidadesRESUMEN
As extracellular vesicles that play an active role in intercellular communication by transferring cellular materials to recipient cells, exosomes offer great potential as a natural therapeutic drug delivery vehicle. The inflammatory responses in various disease models can be attenuated through introduction of super-repressor IκB (srIκB), which is the dominant active form of IκBα and can inhibit translocation of nuclear factor κB into the nucleus. An optogenetically engineered exosome system (EXPLOR) that we previously developed was implemented for loading a large amount of srIκB into exosomes. We showed that intraperitoneal injection of purified srIκB-loaded exosomes (Exo-srIκBs) attenuates mortality and systemic inflammation in septic mouse models. In a biodistribution study, Exo-srIκBs were observed mainly in the neutrophils, and in monocytes to a lesser extent, in the spleens and livers of mice. Moreover, we found that Exo-srIκB alleviates inflammatory responses in monocytic THP-1 cells and human umbilical vein endothelial cells.
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Exosomas/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Sepsis/metabolismo , Sepsis/patología , Animales , Modelos Animales de Enfermedad , Exosomas/ultraestructura , Lipopolisacáridos/efectos adversos , Ratones , Mortalidad , Inhibidor NF-kappaB alfa/administración & dosificación , FN-kappa B/metabolismo , Sustancias Protectoras/administración & dosificación , Sepsis/tratamiento farmacológico , Sepsis/etiología , Transducción de Señal , Distribución TisularRESUMEN
BACKGROUND: Transforming growth factor ß (TGF-ß), retinoic acid (RA), p38 mitogen-activated protein kinase (MAPK), and MEK signaling play critical roles in cell differentiation, proliferation, and apoptosis. We investigated the effect of RA and the role of these signaling molecules on the phosphorylation of Smad2/3 (p-Smad2/3) induced by TGF-ß1. METHODS: A549 epithelial cells and CCD-11Lu fibroblasts were incubated and stimulated with or without all-trans RA (ATRA) and TGF-ß1 and with MAPK or MEK inhibitors. The levels of p-Smad2/3 were analyzed by western blotting. For animal models, we studied three experimental mouse groups: control, bleomycin, and bleomycin+ATRA group. Changes in histopathology, lung injury score, and levels of TGF-ß1 and Smad3 were evaluated at 1 and 3 weeks. RESULTS: When A549 cells were pre-stimulated with TGF-ß1 prior to RA treatment, RA completely inhibited the p-Smad2/3. However, when A549 cells were pre-treated with RA prior to TGF-ß1 stimulation, RA did not completely suppress the p-Smad2/3. When A549 cells were pre-treated with MAPK inhibitor, TGF-ß1 failed to phosphorylate Smad2/3. In fibroblasts, p38 MAPK inhibitor suppressed TGF-ß1-induced p-Smad2. In a bleomycin-induced lung injury mouse model, RA decreased the expression of TGF-ß1 and Smad3 at 1 and 3 weeks. CONCLUSION: RA had inhibitory effects on the phosphorylation of Smad induced by TGF-ß1 in vitro, and RA also decreased the expression of TGF-ß1 at 1 and 3 weeks in vivo. Furthermore, pre-treatment with a MAPK inhibitor showed a preventative effect on TGF-ß1/Smad phosphorylation in epithelial cells. As a result, a combination of RA and MAPK inhibitors may suppress the TGF-ß1-induced lung injury and fibrosis.
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Human papillomavirus (HPV) infection is a co-carcinogen of lung cancer and contributes to its pathogenesis. To evaluate the prevalence of HPV infection, polymerase chain reaction (PCR) was employed to detect HPV 16, 18, and 33 DNA in tumor tissues of 112 patients with non-small cell lung cancer (NSCLC) who underwent curative surgery from Jan. 1995 to Dec. 1998 at Severance Hospital, Seoul, Korea. The patients consisted of 90 men and 22 women. Nineteen patients were under 50 years old (17%), and 92 patients (82%) were smokers. Fifty-three patients had adenocarcinomas, while 59 patients had non-adenocarcinomas. Early stage (I and II) cancer was found in 64 patients (57.1%) and advanced stage (III and IV) found in 48 (42.9%). The prevalence of HPV 16, 18, and 33 were 12 (10.7%), 11 (9.8%), and 37 (33.0%), respectively. Smoking status, sex, and histologic type were not statistically different in the presence of HPV DNA. The presence of HPV 16 was more common in younger patients and HPV 18 was more common in advanced stage patients. This study showed that the prevalence rate of HPV 16 and 18 infections in NSCLC tissue was low, suggesting HPV 16 and 18 infections played a limited role in lung carcinogenesis of Koreans. However, the higher prevalence of HPV 33 infections in Korean lung cancer patients compared to other Asian and Western countries may be important and warrants further investigation.
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Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Neoplasias Pulmonares/epidemiología , Infecciones por Papillomavirus/epidemiología , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Comorbilidad , Femenino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Corea (Geográfico)/epidemiología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa , Prevalencia , Factores Sexuales , FumarRESUMEN
The Eph/ephrin receptor ligand system is known to play a role in inflammation induced by infection, injury, and inflammatory diseases. The present study aimed to evaluate plasma EphA2 receptor levels in critically ill patients with sepsis. This study was a prospective cohort study evaluating samples and clinical data from the medical intensive care unit (MICU) of a 2000-bed university tertiary referral hospital in South Korea. Positive correlations of the plasma EphA2 receptor level with the acute physiology and chronic health evaluation (APACHE) II score and the sequential organ failure assessment (SOFA) score were observed. The area under the curve (AUC) for the plasma EphA2 receptor level on a receiver operating characteristic curve was 0.690 (95% confidence interval [CI], 0.608-0.764); the AUCs for the APACHE II score and SOFA scores were 0.659 (95% CI, 0.576-0.736) and 0.745 (95% CI, 0.666-0.814), respectively. A Cox proportional hazard model identified an association between an increased plasma EphA2 receptor level (>51.5 pg mL-1) and increased risk of 28-day mortality in the MICU (hazard ratio = 3.22, 95% CI, 1.709-6.049). An increased plasma EphA2 receptor level was associated with sepsis severity and 28-day mortality among sepsis patients.
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Efrina-A2/análisis , Choque Séptico/metabolismo , Choque Séptico/mortalidad , APACHE , Anciano , Área Bajo la Curva , Estudios de Cohortes , Enfermedad Crítica/mortalidad , Efrina-A2/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/mortalidad , Puntuaciones en la Disfunción de Órganos , Plasma , Pronóstico , Estudios Prospectivos , Curva ROC , Receptor EphA2 , República de Corea , Factores de Riesgo , Sepsis/mortalidad , Índice de Severidad de la Enfermedad , Choque Séptico/sangreRESUMEN
BACKGROUND: In chronic obstructive pulmonary disease (COPD), the blood vitamin D3 level is generally low, and genetic polymorphisms of vitamin D-binding protein encoded by the GC gene are associated with COPD development. In this study, we examined the relationship between GC polymorphisms and plasma vitamin D3 level in Korean patients with COPD. METHODS: The study included 175 COPD patients from the Korean Obstructive Lung Disease Cohort. Multivariate analysis was conducted with adjustment for age, body mass index (BMI), lung function, smoking status, smoking amount, and seasonal variation in blood vitamin D level. Vitamin D deficiency was defined as a plasma 25-hydroxyvitamin D3 level lower than 20 ng/mL. RESULTS: The mean plasma vitamin D3 level was 17.5 ng/mL. The GC1F variant (44.3%) and genotype 1F-2 (27.4%) were the most common. The plasma vitamin D3 level was lower in patients with the GC2 variant (estimated =-3.73 ng/mL) and higher in those with genotype 1F-1S (estimated =4.08 ng/mL). The GC2 variant was a significant risk factor for vitamin D deficiency (odds ratio =2.41). Among COPD clinical parameters, vitamin D deficiency was associated with a lower ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) regardless of GC polymorphisms. FEV1/FVC was higher in patients with genotype 1F-1F (estimated =3.61%) and lower in those with genotype 1F-2 (estimated =-3.31%). The 6-minute walking distance was shorter for patients with the GC1F variant (estimated =-38.91 m) and longer for those with the GC2 variant (estimated =26.98 m). The emphysema index was higher for patients with the GC1S variant (estimated =6.56%) and genotype 1F-1S (estimated =9.86%), regardless of the vitamin D level. CONCLUSION: The GC2 variant is a risk factor for vitamin D deficiency, and genotype 1F-1S is a protective factor against vitamin D deficiency. GC polymorphisms and vitamin D deficiency correlate with clinical outcomes for Korean patients with COPD.
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Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/sangre , Enfermedad Pulmonar Obstructiva Crónica/genética , Proteína de Unión a Vitamina D/genética , Vitamina D/sangre , Anciano , Femenino , Humanos , Masculino , República de CoreaRESUMEN
BACKGROUND: A recent cytogenetic analysis of non-small cell lung cancer revealed hot-spot regions for deletion on the long arm of chromosome 5 and suggested the existence of putative tumor suppressor genes in that region. However, similar studies on genetic alterations in large cell neuroendocrine carcinoma (LCNEC) have been very limited. To our knowledge, this is the first report to screen for the loss of heterozygosity (LOH) and to examine the location of putative tumor suppressor genes on chromosome 5q in LCNEC. OBJECTIVES: To identify tumor suppressor loci on chromosome 5q in LCNEC by microsatellite analysis. PATIENTS AND METHODS: Microsatellite instability and LOH in tumor and normal tissue samples from 13 patients with LCNEC, who had undergone surgical resections, were analyzed by polymerase chain reaction using a panel of 19 microsatellite DNA markers spanning chromosome 5q. RESULTS: LOH was found in all of the 13 tumors (100%) in at least one informative marker tested. The following four common minimally deleted regions were noticed on chromosome 5q: 5q14.3-q21.1; 5q22.2-q23.1; 5q23.3-q33.2; and 5q35.1-q35.2. Three of 13 individual tumors (23.1%) exhibited shifted bands for at least one of the tested microsatellite markers. Shifted bands occurred in 6 of 224 loci (2.7%) tested. CONCLUSION: These data suggest the presence of at least four tumor suppressor loci on chromosome 5q in LCNEC, and further investigations into cloning candidate tumor suppressor genes are warranted.
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Carcinoma de Células Grandes/genética , Carcinoma Neuroendocrino/genética , Cromosomas Humanos Par 5 , Genes Supresores de Tumor , Neoplasias Pulmonares/genética , Anciano , Mapeo Cromosómico/métodos , Marcadores Genéticos , Humanos , Pérdida de Heterocigocidad , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , FumarRESUMEN
Small cell lung cancer (SCLC) frequently shows a loss of heterozygosity (LOH) on chromosome 15q. In order to define the commonly affected region on chromosome 15q, we tested 23 primary SCLCs by microsatellite analysis. By analyzing 43 polymorphic microsatellite markers located on chromosome 15q, we found that 14 (60.8%) of 23 tumors exhibited a LOH in at least one of the tested microsatellite markers. Two (14.3%) of the 14 tumors were found to have more than a 50% LOH on chromosome 15q. LOH was observed in five commonly deleted regions on 15q. Of those regions, LOH from D15S1012 to D15S1016 was the most frequent (47.8%). LOH was also observed in more than 20-30% of tumors at four other regions, from D15S1031 to D15S1007, from D15S643 to D15S980, from D15S979 to D15S202, and from D15S652 to D15S642. Four of the 23 tumors exhibited shifted bands in at least one of the tested microsatellite markers. Shifted bands occurred in 3.2% (29 of 914) of the loci tested. Our data suggests the presence of at least five tumor suppressor loci on chromosome 15q in SCLC, and further that these may play an important role in SCLC tumorigenesis.
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Carcinoma de Células Pequeñas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 15/genética , Genes Supresores de Tumor , Neoplasias Pulmonares/genética , HumanosRESUMEN
PURPOSE: Autophagy has been reported to be involved in treatment failure in tumor. We aimed to evaluate autophagy activity in tumor tissue and compare them between the recurrence and non-recurrence groups. MATERIALS AND METHODS: We analyzed expressions of autophagy-related proteins in tumor tissues which were obtained from pulmonary metastases of colorectal cancer patients by Western blot. We also analyzed autophagosomes by transmission electron microscopy. RESULTS: Tumor tissues from recurrence group showed increased levels of LC3B-II, decreased levels of p62/SQSTM1, and also a marked accumulation of autophagosomes compared with tissues from non-recurrence group. CONCLUSION: The present study suggests that autophagy may be associated with treatment failure of metastatic colorectal cancer.
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Autofagia , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Proteínas de Microfilamentos/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Anciano , Biomarcadores de Tumor/metabolismo , Western Blotting , Femenino , Humanos , Masculino , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Proyectos Piloto , Proteínas , Estudios Retrospectivos , Proteína Sequestosoma-1 , Insuficiencia del TratamientoRESUMEN
PURPOSE: Multiple genetic factors are associated with chronic obstructive pulmonary disease (COPD). The association of gene encoding vitamin D binding protein (VDBP, GC) with COPD has been controversial. We sought to investigate the types of GC variants in the Korean population and determine the association of GC variants with COPD and lung function in the Korean population. MATERIALS AND METHODS: The study cohort consisted of 203 COPD patients and 157 control subjects. GC variants were genotyped by the restriction fragment-length polymorphism method. Repeated measures of lung function data were analyzed using a linear mixed model including sex, age, height, and pack-years of smoking to investigate the association of GC genetic factors and lung function. RESULTS: GC1F variant was most frequently observed in COPD (46.1%) and controls (42.0%). GC1S variant (29.0% vs. 21.4%; p=0.020) and genotype 1S-1S (8.3% vs. 3.4%; p=0.047) were more commonly detected in control than COPD. According to linear mixed model analysis including controls and COPD, subjects with genotype 1S-1S had 0.427 L higher forced expiratory volume in 1 second (FEV1) than those with other genotypes (p=0.029). However, interaction between the genotype and smoking pack-year was found to be particularly significant among subjects with genotype 1S-1S; FEV1 decreased by 0.014 L per smoking pack-year (p=0.001). CONCLUSION: This study suggested that GC polymorphism might be associated with lung function and risk of COPD in Korean population. GC1S variant and genotype 1S-1S were more frequently observed in control than in COPD. Moreover, GC1S variant was more common in non-decliners than in rapid decliners among COPD.
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Polimorfismo Genético , Enfermedad Pulmonar Obstructiva Crónica/genética , Proteína de Unión a Vitamina D/genética , Anciano , Femenino , Volumen Espiratorio Forzado , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Fumar , Proteína de Unión a Vitamina D/químicaRESUMEN
BACKGROUND: Adenosquamous carcinoma of the lung is composed of adenocarcinomatous and squamous cell carcinomatous components. The epidermal growth factor receptor (EGFR) mutations occur mostly in adenocarcinomas and rarely in squamous cell carcinoma of lung. Attempts to investigate the EGFR mutation status in each component of adenosquamous carcinoma and to characterize the patients according to mutation status may help to understand the histogenesis of adenosquamous carcinoma. METHODS: The mutation status of EGFR kinase domain from exon 18 to 21 was investigated in 25 Korean patients with adenosquamous carcinoma by polymerase chain reaction-single strand conformation polymorphism using the tissues of each component from the adenosquamous carcinoma tumor. Clinicopathologic characteristics of the patients according to the status of EGFR mutations were compared. RESULTS: EGFR mutations were identified in 11 (44%) patients: 9 mutations were in exon 19, 1 in exon 20, and 1 in exon 21. EGFR mutations were significantly more frequent (P = .005) in women (n = 8, 80%) than men (n = 3, 20%). Never-smokers (n = 8, 62%) had EGFR mutations more commonly than smokers (n = 3, 25%; P = .111). Identical EGFR mutations in both components of adenosquamous carcinoma were confirmed by nucleotide sequencing. CONCLUSIONS: The frequency of EGFR mutation and clinicopathologic characteristics of the EGFR mutants in adenosquamous carcinoma are similar to those of Asian patients with adenocarcinomas. Identical EGFR mutations in both components suggest the possibility of monoclonality in the histogenesis of adenosquamous carcinoma.
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Adenocarcinoma/genética , Carcinoma Adenoescamoso/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación/genética , Adenocarcinoma/patología , Adulto , Anciano , Pueblo Asiatico , Carcinoma Adenoescamoso/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Análisis Mutacional de ADN , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
Insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the mitogenic and antiapoptotic activity of insulin-like growth factor (IGF) by blocking the binding of IGF to its receptor. However, under certain circumstances, IGFBP-3 can enhance the activity of IGF by protecting IGF from degradation. More than half of the interindividual variations in IGFBP-3 levels are known to be genetically determined by the polymorphism at -202 locus of IGFBP-3 gene. Therefore, we attempted to ascertain whether the A-202C polymorphic variation of IGFBP-3 gene constitutes a risk factor for non-small cell lung cancer (NSCLC). Our study included 209 NSCLC patients and 209 age-, gender- and smoking status-matched control subjects. The frequencies of each polymorphic variation in the control population were as follows: AA = 95 (45.5%), AC = 91 (43.5%) and CC = 23 (11.0%). In the NSCLC subjects, the genotypic frequencies were as follows: AA = 131 (62.7%), AC = 73 (34.9%) and CC = 5 (2.4%). We detected statistically significant differences in the genotypic distribution between the NSCLC and the control subjects (p < 0.05, Pearson's chi-square test). The NSCLC risk correlated significantly with AA genotype. Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 2.45 (95% CI = 1.17-5.40) and that for the ones with AA genotype was 4.58 (95% CI = 2.17-10.30). These results indicate that the dysregulation of IGF axis should now be considered as another important risk factor for NSCLC and a potential target for novel antineoplastic therapies and/or preventative strategies in high-risk groups.