RESUMEN
Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long-standing UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC-associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia-inducible factor-1α (HIF-1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF-1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.
Asunto(s)
Anhidrasas Carbónicas/metabolismo , Colitis Ulcerosa/complicaciones , Neoplasias Asociadas a Colitis , Neoplasias Colorrectales/diagnóstico , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Western Blotting/métodos , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica IX/metabolismo , Neoplasias Asociadas a Colitis/diagnóstico , Neoplasias Asociadas a Colitis/etiología , Neoplasias Colorrectales/etiología , Humanos , Inmunohistoquímica/métodos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologíaRESUMEN
Our aim was to develop a serodiagnostic marker for lung cancer. Monoclonal antibodies were generated, and one antibody designated as KU-Lu-1, recognizing cytoskeleton-associated protein 4 (CKAP4), was studied further. To evaluate the utility of KU-Lu-1 antibody as a serodiagnostic marker for lung cancer, reverse-phase protein array analysis was performed with sera of 271 lung cancer patients and 100 healthy controls. CKAP4 was detected in lung cancer cells and tissues, and its secretion into the culture supernatant was also confirmed. The serum CKAP4 levels of lung cancer patients were significantly higher than those of healthy controls (P < 0.0001), and the area under the curve of receiver-operating characteristic curve analysis was 0.890, with 81.1% sensitivity and 86.0% specificity. Furthermore, the serum CKAP4 levels were also higher in patients with stage I adenocarcinoma or squamous cell carcinoma than in healthy controls (P < 0.0001). Serum CKAP4 levels may differentiate lung cancer patients from healthy controls, and they may be detected early even in stage I non-small cell lung cancer. Serum CKAP4 levels were also significantly higher in lung cancer patients than in healthy controls in the validation set (P < 0.0001). The present results provide evidence that CKAP4 may be a novel early serodiagnostic marker for lung cancer.
Asunto(s)
Adenocarcinoma/diagnóstico , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Proteínas de la Membrana/sangre , Adenocarcinoma/sangre , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Células Escamosas/sangre , Estudios de Casos y Controles , Humanos , Neoplasias Pulmonares/sangre , Pronóstico , Análisis por Matrices de Proteínas , Células Tumorales CultivadasRESUMEN
We established the KU-Lu-8 monoclonal antibody (MoAb) using a lung cancer cell line as an antigen and a random immunization method. The KU-Lu-8 MoAb recognizes basigin (BSG), which is a transmembrane-type glycoprotein that is strongly expressed on the cell membranes of lung cancer cells. This study aimed to clarify the relationships between BSG expression and clinicopathological parameters and determine the prognostic significance of BSG expression in pulmonary adenocarcinoma (AC) patients. To evaluate the significance of BSG expression in lung cancer, we immunohistochemically analyzed 113 surgically resected pulmonary adenocarcinomas, and the associations between BSG expression and various clinicopathological parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to investigate the effects of BSG expression on survival. Clinicopathologically, BSG expression was significantly associated with tumor differentiation, vascular invasion, lymphatic invasion, and a poor prognosis. In particular, BSG expression was significantly correlated with poorer survival in patients with stage I AC. The high BSG expression group (compared with the low BSG expression group) exhibited adjusted hazard ratios for mortality of 4.694. BSG expression is indicative of a poor prognosis in AC patients, particularly in those with stage I disease.
Asunto(s)
Adenocarcinoma/patología , Basigina/biosíntesis , Biomarcadores de Tumor/análisis , Neoplasias Pulmonares/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Basigina/análisis , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
MAIN CONCLUSION: We identified LSG2 as a novel lytic enzyme that accumulates in the parental extracellular matrix and disrupts parental spheroids cooperatively with VheA secreted by juveniles in Volvox. Spatiotemporally restricted degradation of extracellular matrix (ECM) is essential for development and survival in multicellular organisms. In an asexual life cycle of green algae Volvox, juveniles are released from parental spheroids through holes made by restricted degradation of parental ECM at the proper timing. Lytic enzyme(s) should specifically degrade parental ECM upon Volvox hatching, but little is known about the mechanisms of spatiotemporally restricted parental degradation. Here, we identified a glycoprotein encoded by the Late Somatic Gene 2 (LSG2) as a novel lytic enzyme that accumulates in parental ECM during the prehatching stages. The dual action of LSG2 and Volvox hatching enzyme A (VheA), a serine protease secreted by juveniles, causes the degradation of ECM sheets at all stages and destroys even daughter spheroids, while VheA alone disrupts spheroids only in the prehatching stage when LSG2 is accumulated, suggesting that the combination of LSG2 and VheA is sufficient to cause the degradation of ECM sheet. In the prehatching stage, parental spheroids became susceptible to the proteolysis by a mixture of bacterial proteases applied externally, which could be facilitated by LSG2. These results suggest that LSG2 disrupts parental ECM cooperatively with VheA by modifying the parental ECM to make it fragile, and that the appropriate activity of these enzymes is crucial for the parent-specific ECM degradation at the proper timing.
Asunto(s)
Proteínas Algáceas/metabolismo , Metaloendopeptidasas/metabolismo , Volvox/enzimología , Volvox/genética , Proteínas Algáceas/aislamiento & purificación , Matriz Extracelular/metabolismoRESUMEN
BACKGROUND: Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 (PD-L1) expression in surgically resected NSCLCs. METHODS: We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time. RESULTS: PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group [67%] vs. low expression group [68%]); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026). CONCLUSION: Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.
Asunto(s)
Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/cirugía , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , Adulto , Anciano , Anticuerpos Monoclonales , Antígeno B7-H1/biosíntesis , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVE: High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. METHODS: Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. RESULTS: In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). CONCLUSIONS: This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma Neuroendocrino/diagnóstico , Proteínas Represoras/análisis , Neoplasias del Cuello Uterino/diagnóstico , Carcinoma Neuroendocrino/química , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Papillomaviridae/genética , Neoplasias del Cuello Uterino/químicaRESUMEN
The factors conferring the increased malignancy on lung adenocarcinoma with micropapillary component (AC-MPC) remain to be elucidated. On proteomics based on 2-dimensional gel electrophoresis, 19 proteins differentially expressed by more than 1.5-fold between AC-MPC and conventional adenocarcinoma (CAC); in particular, vimentin, one of the proteins, was 3.5-fold up-regulated in AC-MPC. Subsequent semi-quantitative investigation by immunohistochemistry with large cohorts comprised 101 AC-MPC and 119 CAC, respectively, of different stages revealed that vimentin was expressed in MPC of 95 (94.1%) AC-MPC and the expression scores were higher than those of well- and moderately differentiated CAC, as well as the background non-MPC of the AC-MPC (P < 0.0001), but not significantly different from those of poorly differentiated CAC (P = 0.561). Even within the AC-MPC entity, higher vimentin expression was correlated with more frequent vascular invasion and more advanced node metastasis (P < 0.02), and multivariate analysis showed that high vimentin expression and worse node statuses were independent indicators of adverse prognosis (P < 0.048). In conclusion, vimentin expression is prevalent and markedly up-regulated in MPC, which might reflect the biological essence of poorer differentiation or dedifferentiation of MPC, and this might have a role in the acquisition and increase of invasiveness and consequent more malignant nature of MPC.
Asunto(s)
Adenocarcinoma/patología , Biomarcadores de Tumor/análisis , Carcinoma Papilar/patología , Neoplasias Pulmonares/patología , Vimentina/biosíntesis , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma del Pulmón , Anciano , Carcinoma Papilar/metabolismo , Carcinoma Papilar/mortalidad , Supervivencia sin Enfermedad , Electroforesis en Gel Bidimensional , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Regulación hacia Arriba , Vimentina/análisisRESUMEN
BACKGROUND: Although there are great expectations regarding the use of tumor-infiltrating lymphocytes (TILs) to predict effects of immunotherapies and prognosis, knowledge about TILs remains insufficient for clinical application. METHODS: We objectively investigated the prognostic significance of tumor-infiltrating CD8 + lymphocytes (CD8 + TILs) in squamous cell lung cancer (SQ-LC). Among patients who underwent surgical resection of SQ-LC in 2011-2017, 100 patients with pathological stage IA3-III were immunohistochemically studied to evaluate CD8 + TILs in the tumor stroma and parenchyma. The impact of CD8 + TILs on relapse-free survival was analyzed using a Kaplan-Meier survival analysis and multivariate analyses using Fine-Gray and Cox proportional hazards models. RESULTS: The multivariate analysis showed that large and small numbers, but not intermediate numbers, of CD8 + TILs in the tumor stroma may be related to a more favorable prognosis (small vs. intermediate: HR, 0.64; 95% CI: 0.29-1.41, p = 0.27; large vs. intermediate: HR, 0.48; 95% CI: 0.21-1.09, p = 0.08). In contrast, a large number of CD8 + TILs in the tumor parenchyma was associated with a poor prognosis (HR, 2.60; 95% CI: 0.91-7.42, p = 0.075). An exploratory analysis showed a potentially strong association between an extremely large number of CD8 + TILs in the tumor parenchyma and a poor prognosis, even with a large number of CD8 + TILs in the tumor stroma. CONCLUSION: Our study provided partial but important information on the significance of CD8 + TILs in SQ-LC. To use CD8 + TILs as biomarkers, a better understanding of CD8 + TILs as well as other important components in the tumor microenvironment and the inflammatory phenotypes they form may be needed.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Linfocitos Infiltrantes de Tumor/patología , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Pronóstico , Linfocitos T CD8-positivos/patología , Células Epiteliales/patología , Microambiente TumoralRESUMEN
PURPOSE: Although developing a better understanding of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) might provide essential knowledge to predict response to immunotherapy and prognosis, our current knowledge about Foxp3 + TILs is inadequate. This study investigated the prognostic significance of tumor-infiltrating Foxp3 + lymphocytes (Foxp3 + TILs) in squamous cell lung cancer (SQ-LC) objectively. METHODS: Among patients with SQ-LC surgically resected in our institution between 2011 and 2017, those with pathological stage IA3-IIIA were immunohistochemically studied to evaluate Foxp3 + TILs in their tumor stroma. The impact of Foxp3 + TILs on relapse-free survival (RFS) was analyzed with Kaplan-Meier survival analysis and multivariate analysis using a Cox proportional hazards model/Fine-Gray model. RESULTS: This study analyzed 100 patients. Multivariate analysis showed that a large number of Foxp3 + TILs in the stroma does not associate with a poor prognosis, rather that a large number of Foxp3 + TILs (≥ 64 cells) tend to be associated with a more favorable prognosis than a small number of Foxp3 + TILs (< 64 cells) (large vs small number: HR, 0.56; 95% CI, 0.17-1.83; P = 0.34). Exploratory analysis also showed that in the two populations divided by a difference in Foxp3 expression levels, similar trends to the main analysis were observed. CONCLUSION: Our results showed that a large number of Foxp3 + TILs in the stroma may not associate with a poor prognosis in SQ-LC. To use the seemingly complicated information of Foxp3 + TILs as biomarkers, better understanding the diversity and heterogeneity of Foxp3 + TILs and analyzing their subpopulations that increase in the TME may be needed.
Asunto(s)
Carcinoma de Células Escamosas , Factores de Transcripción Forkhead , Estimación de Kaplan-Meier , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Factores de Transcripción Forkhead/metabolismo , Masculino , Femenino , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Anciano , Persona de Mediana Edad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Pronóstico , Estudios Retrospectivos , Modelos de Riesgos Proporcionales , Anciano de 80 o más Años , AdultoRESUMEN
Pulmonary papillary adenoma is a rare tumor. We analyzed a tumor which appeared in a 16-year-old Japanese woman. The tumor histologically showed papillary proliferation of one-layered tumor cells coating inflammatory fibrovascular cores. At the periphery of the tumor, the tumor cells grew in a lepidic fashion. The tumor cells were confirmed as type-II pneumocytes with electron-microscope. In this study, using immunohistochemistry, in situ hybridization and real-time reverse transcription polymerase chain reaction, we examined the expressions and quantities of fibroblast growth factor 10 (FGF10), keratinocyte growth factor (KGF) and fibroblast growth factor receptor 2 (FGFR2) IIIb, based on the extent of their abilities of proliferation and differentiation of type II pneumocytes. The tumor cells expressed FGFR 2 and produced 350 times more FGFR2IIIb messenger RNA (mRNA) than did the nontumorous lung. The quantity of KGF mRNA in the tumor tissue was twice that of the nontumorous lung. Moreover, there was dysregulation of FGFR2IIIb transcription in the tumor. According to these findings, we expect overexpression of FGFR2IIIb to play an important role in causing tumor. Because FGFR is suspected to be connected with lung carcinoma, we also treat similar tumorigenesis via FGFR as carcinoma; complete resection of adenoma might be indicated.
Asunto(s)
Adenoma/patología , Transformación Celular Neoplásica/patología , Factores de Crecimiento de Fibroblastos/metabolismo , Neoplasias Pulmonares/patología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Adenoma/metabolismo , Adenoma/cirugía , Adolescente , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/ultraestructura , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/metabolismo , Femenino , Expresión Génica , Humanos , Recién Nacido , Pulmón/embriología , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirugía , ARN Mensajero/metabolismo , Radiografía Torácica , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Tomografía Computarizada por Rayos XRESUMEN
The overexpression of DJ-1 protein and its secretion into the bloodstream has been reported in various neoplasms. However, serum levels and the subcellular localization of DJ-1 have not been analyzed in detail in bladder cancer (BC). Our comprehensive analysis of these variables started with the measurement of DJ-1 in serum from 172 patients with BC, 20 patients with urolithiasis and 100 healthy participants. Next, an immunohistochemical study of DJ-1 expression and localization was conducted in 92 patients with BC, and associations with clinicopathologic factors and patient outcomes were evaluated. Serum DJ-1 was significantly higher in patients with BC than in those with urolithiasis or in healthy participants. Immunohistochemically, a cytoplasm-positive (Cy+) and nucleus-negative (N-) DJ-1 pattern was associated with age and pathologic stage. Log-rank tests indicated that the Cy+, N- pattern was significantly associated with overall survival (OS), recurrence-free survival (RFS), and cancer specific survival (CSS). In addition, the Cy+, N- pattern was an independent prognostic factor in the multivariate analysis adjusted for the effects of the clinicopathologic outcomes. The investigation of DJ-1 expression might help physicians to make decisions regarding further follow-up and additional treatments.
RESUMEN
The aim of this study was to clarify the genetic backgrounds underlying the clinicopathological characteristics of urothelial carcinomas (UCs). Array comparative genomic hybridization analysis using a 244K oligonucleotide array was performed on 49 samples of UC tissue. Losses of 2q33.3-q37.3, 4p15.2-q13.1 and 5q13.3-q35.3 and gains of 7p11.2-q11.23 and 20q13.12-q13.2 were correlated with higher histological grade, and gain of 7p21.2-p21.12 was correlated with deeper invasion. Losses of 6q14.1-q27 and 17p13.3-q11.1 and gains of 19q13.12-q13.2 and 20q13.12-q13.33 were correlated with lymph vessel involvement. Loss of 16p12.2-p12.1 and gain of 3q26.32-q29 were correlated with vascular involvement. Losses of 5q14.1-q23.1, 6q14.1-q27, 8p22-p21.3, 11q13.5-q14.1 and 15q11.2-q22.2 and gains of 7p11.2-q11.22 and 19q13.12-q13.2 were correlated with the development of aggressive non-papillary UCs. Losses of 1p32.2-p31.3, 10q11.23-q21.1 and 15q21.3 were correlated with tumor recurrence. Unsupervised hierarchical clustering analysis based on copy number alterations clustered UCs into three subclasses: copy number alterations associated with genome-wide DNA hypomethylation, regional DNA hypermethylation on C-type CpG islands and genome-wide DNA hypo- and hypermethylation were accumulated in clusters A, B(1) and B(2), respectively. Tumor-related genes that may encode therapeutic targets and/or indicators useful for the diagnosis and prognostication of UCs should be explored in the above regions. Both genetic and epigenetic events appear to accumulate during urothelial carcinogenesis, reflecting the clinicopathological diversity of UCs.
Asunto(s)
Metilación de ADN , Dosificación de Gen , Neoplasias de la Vejiga Urinaria/genética , Anciano , Anciano de 80 o más Años , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Familia de Multigenes , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
For appropriate surveillance of patients at the precancerous stage for hepatocellular carcinomas (HCCs), carcinogenetic risk estimation is advantageous. The aim of our study was to establish criteria for such estimation based on DNA methylation profiling. The DNA methylation status of 203 CpG sites on 25 bacterial artificial chromosome (BAC) clones, whose DNA methylation status had been proven to discriminate samples of noncancerous liver tissue obtained from patients with HCC (N) from normal liver tissue (C) samples by BAC array-based methylated CpG island amplification, was evaluated quantitatively using pyrosequencing. The 45 CpG sites whose DNA methylation levels differed significantly between C and N in the learning cohort (n=22) were identified. The criteria combining DNA methylation status for the 30 regions including the 45 CpG sites were able to diagnose N as being at high risk of carcinogenesis with 100% sensitivity and specificity in the learning cohort and 95.6% sensitivity and 100% specificity in the validation (n=90) cohort. DNA methylation status for the 30 regions in N samples was significantly correlated with the outcome of patients with HCCs, indicating that clinicopathologically valid DNA methylation alterations have already accumulated at the precancerous stage. The DNA methylation status of the 30 regions did not depend on the presence or absence of hepatitis virus infection, or the status of noncancerous liver tissue (chronic hepatitis or cirrhosis). These criteria may be applicable for carcinogenetic risk estimation using liver biopsy specimens obtained from patients who are followed up because of chronic liver diseases.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiología , Islas de CpG , Metilación de ADN , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/etiología , Hígado/patología , Lesiones Precancerosas/etiología , Anciano , Cromosomas Artificiales Bacterianos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Lesiones Precancerosas/diagnóstico , Pronóstico , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Galectin-3 (GAL3), a protein encoded by the LGALS3 gene, plays diverse roles in cancer initiation, progression, and drug resistance. Accordingly, high GAL3 expression in tumor cells is associated with poor prognosis in non-small cell lung cancer (NSCLC). However, the prognostic impact of GAL3 expression on patients with resected NSCLC receiving platinum-based adjuvant chemotherapy (AC) remains unclear. This study aimed to determine the prognostic significance of GAL3 expression in NSCLC patients receiving platinum-based AC. METHODS: The study included 111 patients with completely resected stages II and IIIA NSCLC who were receiving platinum-based AC. GAL3 expression in cancer cells was evaluated immunohistochemically according to H-score ("histo score), with a score of ≥170 considered as high expression. The correlation of GAL3 expression with clinicopathological characteristics and survival was subsequently evaluated. RESULTS: In survival analysis, GAL3 expression was significantly associated with recurrence-free survival (RFS) and overall survival (OS). In multivariate analysis, GAL3 expression was an independent predictive factor of RFS rather than OS. CONCLUSIONS: GAL3 expression is a reliable biomarker to predict the prognosis of completely resected NSCLC patients receiving platinum-based AC.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Galectinas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioterapia Adyuvante , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2-D gel electrophoresis (2-DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2-DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin-fixed and paraffin-embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC (P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Grandes/metabolismo , Carcinoma Neuroendocrino/metabolismo , Queratinas/biosíntesis , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Carcinoma de Células Grandes/patología , Carcinoma Neuroendocrino/patología , Electroforesis en Gel Bidimensional , Humanos , Inmunohistoquímica , Queratina-18/biosíntesis , Queratina-19/biosíntesis , Queratina-7/biosíntesis , Queratina-8/biosíntesis , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Análisis de Matrices TisularesRESUMEN
NAP1L1 is a key regulator of embryonic neurogenesis but its role in lung cancer remains unexplored. In this study, we investigated the relationship between NAP1L1 expression and the clinicopathological parameters and prognosis of non-small cell lung cancer patients. To this end, the expression of NAP1L1 in tumor samples was evaluated by immunohistochemistry. NAP1L1 expression was significantly associated with reduced differentiation (P = 0.00014), higher pathological TNM stages (P < 0.00001), lymph node metastasis (P < 0.00001), intrapulmonary metastasis (P = 0.02955), lymphatic invasion (P = 0.00019), vascular invasion (P = 0.00008) and poorer prognosis (P = 0.0008) of patients with adenocarcinoma. Moreover, multivariate analyses using the Cox-proportional hazards model confirmed that NAP1L1 expression increased the risk of death after adjusting for other clinicopathological factors (HR = 2.46, 95% CI, 1.22-4.96). Furthermore, NAP1L1 expression was identified as an independent poor prognostic factor in patients with resectable stage I lung adenocarcinoma. NAP1L1-siRNA-treated lung adenocarcinoma-derived A549 cells showed significant suppression of proliferation, migration, and invasion abilities. These findings suggest that NAP1L1 may be a novel predictive and prognostic marker in lung adenocarcinoma, particularly in those with stage I of the disease.
Asunto(s)
Adenocarcinoma del Pulmón/diagnóstico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Proteína 1 de Ensamblaje de Nucleosomas/genética , Células A549 , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular , Proliferación Celular , Detección Precoz del Cáncer/métodos , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Proteína 1 de Ensamblaje de Nucleosomas/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Platinum-based adjuvant chemotherapy after complete resection has become a standard treatment for patients with stage II to IIIA non-small cell lung cancer; however, not all patients exhibit survival benefits. Therefore, the development of predictive biomarkers for selecting a subgroup of patients who may show improved survival after these treatments is important. Among the 42 proteins identified here using a proteomics analysis that were recognized by autoantibodies in pretreated sera from patients with lung adenocarcinoma who received platinum-based adjuvant chemotherapy, the tumor necrosis factor-receptor-associated protein 1 (TRAP1) was detected in patients with a short disease-free survival. TRAP1 expression was immunohistochemically analyzed in 64 patients with completely resected stage II and IIIA lung adenocarcinoma treated with platinum-based adjuvant chemotherapy. TRAP1 expression was significantly associated with higher p-TNM stage (P = 0.005) and lymph node metastasis (P = 0.017). Moreover, TRAP1 expression was significantly correlated with a shorter disease-free survival (P = 0.028). Furthermore, TRAP1-siRNA-treated LC-2/ad cells derived from lung adenocarcinoma exhibited significantly reduced proliferation and increased sensitivity to cisplatin. These results suggest that TRAP1 expression is a valuable biomarker for predicting the poor survival of platinum-based adjuvant chemotherapy in patients with resected lung adenocarcinoma.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/cirugía , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/métodos , Proteínas HSP90 de Choque Térmico/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Células A549 , Adulto , Anciano , Cisplatino/farmacología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Electroforesis en Gel Bidimensional , Femenino , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Proteómica/métodos , ARN Interferente Pequeño/metabolismo , Estudios RetrospectivosRESUMEN
The prognosis of malignant neuroendocrine tumors of the lung is known to be very poor. Aiming to identify new markers of pulmonary neuroendocrine tumors in early stages and also differential diagnostic markers between large cell neuroendocrine carcinoma and small cell lung cancer, we comprehensively analyzed peptides which were secreted into conditioned medium by LCN1, a large cell neuroendocrine carcinoma cell line. Specific peaks in conditioned medium but not in used medium alone were detected using matrix-associated laser desorption/ionization time of flight mass spectrometry. Two peptide fragments of 40 and 19 amino acid residues were identified by matrix-associated laser desorption/ionization time of flight mass spectrometry. These two fragments were demonstrated to be parts of VGF nerve growth factor inducible (VGF), which is usually expressed in nerve cells or neuroendocrine cells. RT-PCR analysis of lung cancer cell lines showed that VGF mRNA was expressed only in neuroendocrine carcinoma-derived cells. Our data suggest that VGF can be used as a novel serological diagnostic marker of pulmonary neuroendocrine tumors.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Células Grandes/diagnóstico , Carcinoma Neuroendocrino/diagnóstico , Neoplasias Pulmonares/diagnóstico , Factor A de Crecimiento Endotelial Vascular/análisis , Secuencia de Aminoácidos , Carcinoma de Células Grandes/metabolismo , Carcinoma Neuroendocrino/metabolismo , Línea Celular Tumoral , Medios de Cultivo Condicionados , Humanos , Neoplasias Pulmonares/metabolismo , Datos de Secuencia Molecular , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Factor A de Crecimiento Endotelial Vascular/química , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Changes in cerebrospinal fluid (CSF) composition have been shown to accurately reflect pathological processes in the CNS, and are potential indicators of abnormal CNS states, such as tumor growth. To detect biomarkers in high-grade astrocytomas, the differential expression of proteins in the cerebrospinal fluid was analyzed from two cases each of diffuse astrocytoma (grade II), and glioblastoma (grade IV) using agarose 2-D gel electrophoresis (2-DE). It was found that the expression of gelsolin protein decreased with histological grade. To examine whether gelsolin is a useful indicator of tumor aggressiveness or patient outcome, its expression was further studied on immunohistochemistry in 41 formalin-fixed and paraffin-embedded astrocytomas. The positive cell rate of gelsolin in tumors was 59.4% in grade II, 30.0% in grade III and 29.4% in grade IV, respectively. Gelsolin expression was significantly lower in high-grade astrocytomas (grade III or IV) than in low-grade astrocytomas (grade II; P < 0.05). Moreover, in astrocytomas the overall survival of patients in the low-expression group was significantly poorer than in the high expression group (P < 0.05). These data suggest that gelsolin is a prognostic factor in astrocytoma.
Asunto(s)
Astrocitoma/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Encefálicas/líquido cefalorraquídeo , Gelsolina/líquido cefalorraquídeo , Astrocitoma/mortalidad , Astrocitoma/patología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Electroforesis en Gel Bidimensional , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Pronóstico , Proteómica , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
This study aimed to clarify relationships among UDP-glucose-6 dehydrogenase (UGDH) expression, clinicopathological factors, and the prognosis of patients, and to determine the role of UGDH in lung adenocarcinoma (AC). Firstly, UGDH expression and localization in 126 lung AC tissues were immunohistochemically studied, and associations with clinicopathological parameters and patients' prognosis were evaluated. Secondly, serum UGDH levels were measured in 267 lung cancer patients and 100 healthy controls. Finally, the effects of UGDH knockdown by siRNA on migration and invasion abilities were analyzed. As a result, nuclear UGDH staining was significantly correlated with poorer differentiation, a larger tumor size, higher p-TNM stage, positive nodal metastasis, positive lymphatic invasion, and positive vascular invasion in lung AC patients. Nuclear UGDH-positive patients showed significantly poorer survival than nuclear UGDH-negative patients. Serum UGDH levels were especially higher in lung AC patients even in stage I than those in healthy controls. In lung AC cell lines, nuclear expression levels of UGDH were higher in LC-2/ad cells than in A549 cells. UGDH siRNA-treated LC-2/ad cells showed significantly decreased migration and invasion abilities, but no significant differences were observed in UGDH siRNA-treated A549 cells. These data indicate that UGDH expression and localization are an early sero-diagnostic marker in addition to a poor prognostic indicator in lung AC patients.