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1.
Gastric Cancer ; 21(5): 765-775, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29468422

RESUMEN

BACKGROUND: We attempted to identify the molecular profiles of gastric intramucosal neoplasia (IMN; low-grade dysplasia, LGD; high-grade dysplasia, HGD; intramucosal cancer, IMC) by assessing somatic copy number alterations (SCNAs) stratified by microsatellite status (microsatellite stable, MSS; microsatellite instable, MSI). Thus, microsatellite status was determined in 84 tumors with MSS status and 16 tumors with MSI status. METHODS: One hundred differentiated type IMNs were examined using SCNAs. In addition, genetic mutations (KRAS, BRAF, PIK3CA, and TP53) and DNA methylation status (low, intermediate and high) were also analyzed. Finally, we attempted to identify molecular profiles using a hierarchical clustering analysis. RESULTS: Three patterns could be categorized according to SCNAs in IMNs with the MSS phenotype: subgroups 1 and 2 showing a high frequency of SCNAs, and subgroup 3 displaying a low frequency of SCNAs (subgroup 1 > 2 > 3 for SCNA). Subgroup 1 could be distinguished from subgroup 2 by the numbers of total SCNAs (gains and losses) and SCN gains (subgroup 1 > 2). The SCNA pattern of LGD was different from that of HGD and IMC. Moreover, IMNs with the MSI phenotype could be categorized into two subtypes: high frequency of SCNAs and low frequency of SCNAs. Genetic mutations and DNA methylation status did not differ among subgroups in IMNs. CONCLUSION: Molecular profiles stratified by SCNAs based on microsatellite status may be useful for elucidation of the mechanisms of early gastric carcinogenesis.


Asunto(s)
Variaciones en el Número de Copia de ADN , Repeticiones de Microsatélite , Neoplasias Gástricas/genética , Anciano , Anciano de 80 o más Años , Fosfatidilinositol 3-Quinasa Clase I/genética , Análisis por Conglomerados , Metilación de ADN , Femenino , Mucosa Gástrica/patología , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Gástricas/patología , Proteína p53 Supresora de Tumor/genética
2.
Gastric Cancer ; 20(2): 286-296, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27236438

RESUMEN

BACKGROUND: Although genetic alterations in patients with advanced gastric cancer have been extensively studied, those in patients with intramucosal neoplasia (IMN) are still poorly understood. METHODS: We evaluated genetic differences in 158 IMNs, including 51 low-grade dysplasias, 58 high-grade dysplasias (HGDs), 30 intramucosal cancers (IMCs), and 19 mixed tumors (composed of IMC and HGD within the same tumor), using PCR-based microsatellite analysis [allelic imbalance (AI) and microsatellite instability (MSI)]. We classified the DNA methylation status as a hypermethylated epigenome, a moderately methylated epigenome, or a hypomethylated epigenome. In addition, p53 overexpression, ß-catenin nuclear localization, and mucin expression were also examined. RESULTS: From cluster analysis, the IMNs examined were categorized into four subgroups as follows. Tumors in subgroup 1 were characterized by MSI-high status, a hypermethylated epigenome, and loss or reduction of expression of MLH-1. Tumors in subgroup 2 showed a mixed pattern consisting of AI and MSI. In contrast, tumors in subgroup 3, which showed accumulation of multiple AIs, were closely associated with HGD, IMC, or mixed tumor and exhibited nuclear expression of ß-catenin. Tumors in subgroup 4, which were generally low-grade dysplasias, exhibited a low frequency of AIs and no MSI. Although the mucin phenotype was not correlated with any subgroup, expression of mucin was associated with some subgroups. Overexpression of p53 was common in all subgroups. CONCLUSION: The approach described herein was useful for studying genetic differences in IMNs. In addition, we suggest that stratification of genetic differences may help to identify genetic molecular profiles in IMNs.


Asunto(s)
Biomarcadores de Tumor/genética , Transformación Celular Neoplásica/genética , Metilación de ADN , Mucosa Gástrica/metabolismo , Inestabilidad de Microsatélites , Neoplasias Gástricas/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Resección Endoscópica de la Mucosa , Femenino , Estudios de Seguimiento , Mucosa Gástrica/patología , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía
3.
Int J Cancer ; 138(7): 1689-97, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26538087

RESUMEN

The relevance of the clinicopathological and molecular features of early gastric cancers (EGCs) having the microsatellite instability (MSI)-high phenotype has not been clearly defined in sporadic gastric carcinogenesis. Here, we examined the clinicopathological and molecular characteristics of EGC according to MSI status in 330 patients with EGC (intestinal-type adenocarcinoma). Tumors were classified as MSI-high (45 cases), MSI-low (9 cases), or microsatellite stable (MSS; 276 cases). The specimens were examined using a combination of polymerase chain reaction (PCR)-microsatellite assays and PCR-pyrosequencing to detect chromosomal allelic imbalances in multiple cancer-related chromosomal loci, MSI, gene mutations (KRAS and BRAF) and methylation status [high methylation epigenome (HME), intermediate methylation epigenome and low methylation epigenome]. In addition, the expression levels of various target proteins were examined using immunohistochemistry. Interestingly, EGC with the MSI phenotype showed distinct papillary features. The expression of gastric mucin was more frequent in EGC with the MSI phenotype, while p53 overexpression was common in EGCs, irrespective of MSI status. The frequency of HME was significantly higher in EGCs with the MSI phenotype than in EGCs with the MSS phenotype. Although there was a low frequency of allelic imbalance in EGCs with the MSI phenotype, some markers of allelic imbalance were more frequently detected in EGCs with the MSI-high phenotype than in EGCs with the MSS phenotype. KRAS and BRAF mutations were rare in EGCs. Thus, the MSI phenotype in EGC is a major precursor lesion in gastric cancer and is characterized by distinct clinicopathological and molecular features.


Asunto(s)
Adenocarcinoma/genética , Adenocarcinoma/patología , Inestabilidad de Microsatélites , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Reacción en Cadena de la Polimerasa
4.
Int J Cancer ; 127(11): 2500-9, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20178104

RESUMEN

Identification of the molecular characteristics of intramucosal (IMCs) and submucosal cancers (SMCs) is essential to our understanding of early gastric carcinogenesis. However, little is known regarding the differences between the 2 lesions. One hundred and forty-eight patients with primary early gastric cancer [IMC, 106; SMC, 42] were characterized for expression of cell cycle-related proteins and loss of heterozygosity (LOH). We also examined microsatellite instability (MSI) and methylation status. For LOH and methylation studies, we used a panel of 17 microsatellite markers (3p, 4p, 5q, 9p. 13q, 17p, 18q and 22q) and promoter regions of 9 genes (MLH-1, RUNX3, p16, HPP1, RASSF2A, SFRP1, DKK-1, ZFP64 and SALL4) that are frequently altered or methylated in gastric cancers. Overexpression of p53 and cyclin D1 was observed in SMC. In addition, low expression of p27 was more frequent in SMC than in IMC. Frequencies of 4p, 9p, 13q and 22q were significantly higher in SMC than in IMC. The SALL4 gene was frequently methylated in SMC compared with IMC. However, other gene methylations were common in both IMC and SMC. The frequency of LOH-high status/methylation-low status was significantly higher in SMC than in IMC. However, LOH-low status/methylation-high status in SMC was more frequently found in IMC. Our data confirm that methylation of cancer-related genes plays a major role in the development of IMCs. Importantly, the results also show that gastric submucosal progression is characterized by the accumulation of specific genetic alterations. In addition, changes of cell cycle-related proteins are associated with cancer progression.


Asunto(s)
Mucosa Gástrica/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Metilación de ADN , Femenino , Mucosa Gástrica/metabolismo , Humanos , Inmunohistoquímica , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/metabolismo
5.
BMC Gastroenterol ; 10: 55, 2010 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-20525401

RESUMEN

BACKGROUND: Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes. METHODS: Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and beta-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined. RESULTS: Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined. CONCLUSIONS: Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers.


Asunto(s)
Adenocarcinoma/metabolismo , Proteínas de Ciclo Celular/metabolismo , Mucinas Gástricas/metabolismo , Fenotipo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patología , Diferenciación Celular , Ciclina A/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Antígeno Nuclear de Célula en Proliferación/metabolismo , Neoplasias Gástricas/patología , Proteína p53 Supresora de Tumor/metabolismo
6.
Mol Cell Biol ; 25(15): 6834-45, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16024815

RESUMEN

AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.


Asunto(s)
Proteínas de Unión al ADN/genética , Infertilidad Masculina/genética , Leucemia/genética , Proto-Oncogenes/genética , Espermatogénesis/genética , Factores de Transcripción/genética , Translocación Genética , Animales , Apoptosis/genética , Marcación de Gen , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Proteína de la Leucemia Mieloide-Linfoide , Espermatozoides/fisiología , Testículo/metabolismo , Factores de Transcripción/metabolismo , Factores de Elongación Transcripcional
7.
Mol Cell Biol ; 23(6): 1863-73, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12612062

RESUMEN

The multisubunit transcription elongation factor NELF (for negative elongation factor) acts together with DRB (5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) sensitivity-inducing factor (DSIF)/human Spt4-Spt5 to cause transcriptional pausing of RNA polymerase II (RNAPII). NELF activity is associated with five polypeptides, A to E. NELF-A has sequence similarity to hepatitis delta antigen (HDAg), the viral protein that binds to and activates RNAPII, whereas NELF-E is an RNA-binding protein whose RNA-binding activity is critical for NELF function. To understand the interactions of DSIF, NELF, and RNAPII at a molecular level, we identified the B, C, and D proteins of human NELF. NELF-B is identical to COBRA1, recently reported to associate with the product of breast cancer susceptibility gene BRCA1. NELF-C and NELF-D are highly related or identical to the protein called TH1, of unknown function. NELF-B and NELF-C or NELF-D are integral subunits that bring NELF-A and NELF-E together, and coexpression of these four proteins in insect cells resulted in the reconstitution of functionally active NELF. Detailed analyses using mutated recombinant complexes indicated that the small region of NELF-A with similarity to HDAg is critical for RNAPII binding and for transcriptional pausing. This study defines several important protein-protein interactions and opens the way for understanding the mechanism of DSIF- and NELF-induced transcriptional pausing.


Asunto(s)
Extensión de la Cadena Peptídica de Translación/fisiología , Proteínas Represoras , Factores de Transcripción/química , Secuencia de Aminoácidos , Clonación Molecular , Evolución Molecular , Humanos , Sustancias Macromoleculares , Modelos Biológicos , Datos de Secuencia Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Factor B de Elongación Transcripcional Positiva , Mapeo de Interacción de Proteínas , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Subunidades de Proteína , ARN Polimerasa II/química , ARN Polimerasa II/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Análisis de Secuencia de Proteína , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Factores de Elongación Transcripcional
8.
Mol Cell Biol ; 24(8): 3324-36, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15060154

RESUMEN

Recent studies have suggested that Spt6 participates in the regulation of transcription by RNA polymerase II (RNAPII). However, its underlying mechanism remains largely unknown. One possibility, which is supported by genetic and biochemical studies of Saccharomyces cerevisiae, is that Spt6 affects chromatin structure. Alternatively, Spt6 directly controls transcription by binding to the transcription machinery. In this study, we establish that human Spt6 (hSpt6) is a classic transcription elongation factor that enhances the rate of RNAPII elongation. hSpt6 is capable of stimulating transcription elongation both individually and in concert with DRB sensitivity-inducing factor (DSIF), comprising human Spt5 and human Spt4. We also provide evidence showing that hSpt6 interacts with RNAPII and DSIF in human cells. Thus, in vivo, hSpt6 may regulate multiple steps of mRNA synthesis through its interaction with histones, elongating RNAPII, and possibly other components of the transcription machinery.


Asunto(s)
ARN Polimerasa II/metabolismo , Proteínas Represoras , Transcripción Genética , Factores de Elongación Transcripcional/metabolismo , Animales , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Células HeLa , Chaperonas de Histonas , Humanos , Técnicas In Vitro , Sustancias Macromoleculares , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción , Factores de Elongación Transcripcional/genética
12.
Pathol Int ; 54(6): 425-35, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15144402

RESUMEN

There are differing views between Western and Japanese pathologists on the use of histological criteria to classify gastrointestinal tumors. It is therefore a priority to create a new histological classification of the stomach in order to resolve the confusion. Expression patterns were examined of mucin (MUC2, CD10, MUC5AC, pyloric gland-type mucin), p53 protein, and Ki-67 in tumor cells according to the following new classification system for differentiated-type intramucosal neoplastic lesions of the stomach, based on nuclear atypia: borderline neoplasia (adenoma (including dysplasia), indefinite tumor of adenoma or low-grade cancer, and low-grade cancer) and definite carcinoma (intermediate cancer, and high-grade cancer). The resulting grades were: adenoma, 23; indefinite tumor for adenoma or low-grade cancer, 6; low-grade cancer, 28; intermediate cancer, 48; high-grade cancer, 20. While the frequency of intestinal-type borderline neoplasias was higher than that of definite carcinomas, the mixed-type of definite carcinomas occurred with higher frequency than borderline neoplasias. The p53 protein overexpression and the Ki-67-positive rate increased with an increase in the grade assigned according to the new classification. The correlated expression levels of p53 protein, Ki-67, and various mucins, support the conclusion that this classification of intramucosal neoplastic lesions is useful for obtaining a consensus diagnosis of gastric intramucosal neoplasia between pathologists and gastrointestinal clinicians.


Asunto(s)
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Mucinas Gástricas/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Gástricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adenocarcinoma/clasificación , Adenocarcinoma/patología , Adenoma/clasificación , Adenoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Gastroscopía , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Gástricas/clasificación , Neoplasias Gástricas/patología
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