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1.
J Natl Cancer Inst ; 116(5): 681-693, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38258659

RESUMEN

BACKGROUND: Intestinal metaplasia (IM) and intraepithelial neoplasia (IEN) are considered precursors of gastric cardia cancer (GCC). Here, we investigated the histopathologic and molecular profiles of precancerous gastric cardia lesions (PGCLs) and biomarkers for risk stratification of gastric cardia IM. METHODS: We conducted a hospital-based evaluation (n = 4578) for PGCL profiles in high-incidence and non-high-incidence regions for GCC in China. We next performed 850K methylation arrays (n = 42) and RNA-seq (n = 44) in tissues with PGCLs. We then examined the protein expression of candidate biomarker using immunohistochemistry. RESULTS: Of the 4578 participants, 791 were diagnosed with PGCLs (600 IM, 62 IM with IEN, and 129 IEN). We found that individuals from high-incidence regions (26.7%) were more likely to develop PGCLs than those from non-high-incidence areas (13.5%). DNA methylation and gene expression alterations, indicated by differentially methylated probes (DMPs) and differentially expressed genes (DEGs), exhibited a progressive increase from type I IM (DMP = 210, DEG = 24), type II IM (DMP = 3402, DEG = 129), to type III IM (DMP = 3735, DEG = 328), peaking in IEN (DMP = 47 373, DEG = 2278). Three DEGs with aberrant promoter methylation were identified, shared exclusively by type III IM and IEN. Of these DEGs, we found that OLFM4 expression appears in IMs and increases remarkably in IENs (P < .001). CONCLUSIONS: We highlight that type III IM and IEN share similar epigenetic and transcriptional features in gastric cardia and propose biomarkers with potential utility in risk prediction.


Asunto(s)
Cardias , Metilación de ADN , Lesiones Precancerosas , Neoplasias Gástricas , Transcriptoma , Humanos , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Cardias/patología , Cardias/metabolismo , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Metaplasia/genética , Metaplasia/patología , Regulación Neoplásica de la Expresión Génica , Adulto , Incidencia , Anciano , Carcinoma in Situ/genética , Carcinoma in Situ/patología
2.
J Natl Cancer Inst ; 116(2): 299-308, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-37699004

RESUMEN

BACKGROUND: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer . METHODS: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction. RESULTS: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78). CONCLUSIONS: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.


Asunto(s)
Adenocarcinoma , Carcinoma de Células en Anillo de Sello , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/genética , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/genética , Adenocarcinoma/epidemiología , Adenocarcinoma/genética , Cardias/metabolismo , Unión Esofagogástrica/metabolismo , Unión Esofagogástrica/patología , Carcinoma de Células en Anillo de Sello/metabolismo , Carcinoma de Células en Anillo de Sello/patología , Estudios Retrospectivos
3.
Gut ; 73(1): 63-77, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-36977555

RESUMEN

OBJECTIVE: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.


Asunto(s)
Adenocarcinoma , Neoplasias Gástricas , Humanos , Cardias/metabolismo , S-Adenosilmetionina , Células Madre Neoplásicas/metabolismo , Niacinamida , Nicotinamida N-Metiltransferasa/genética , Nicotinamida N-Metiltransferasa/metabolismo , Acuaporina 5
4.
J Clin Lab Anal ; 36(9): e24617, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35870178

RESUMEN

OBJECTIVES: To investigate the function of PAQR3 in gastric cardia adenocarcinoma (GCA) and understand the possible mechanism of PAQR3 in regulating epithelial-mesenchymal transition (EMT). METHODS: We detected PAQR3 protein in 146 GCA tissues and paired normal adjacent tissues (PNTs) specimens using immunohistochemical analysis, and explored its clinical significance. The expression levels of PAQR3 protein in 20 GCA tissues, their paired PNTs, HGC27, SGC7901, and GES-1 cells were analyzed by Western blot. Wild-type PAQR3 was overexpressed in HGC27 cells. The effects of PAQR3 overexpression on the function of HGC27 cells and its underlying mechanisms were then analyzed through a series of cell and molecular biology experiments. RESULTS: PAQR3 was significantly down-regulated in GCA tissues when compared with paired PNTs (p < 0.0001). The expression level of PAQR3 in GCA tissues was significantly negatively correlated with Helicobacter pylori infection (p = 0.000), venous invasion (p = 0.000), invasion depth (p = 0.000), lymph node metastasis (p = 0.022), tumor stage (p = 0.000), and patient survival (p = 0.009). Downregulation of PAQR3 was highly correlated with increased EMT signature and activated TGF-ß/Smad pathway in GCA tissues. Overexpression of PAQR3 in HGC27 cells negatively regulates its cellular functions, such as cell proliferation and migration, and suppresses EMT. Mechanistically, overexpression of PAQR3 significantly down-regulates the protein expression levels of TGF-1, p-Smad2, and p-Smad3 in HGC27 cells. CONCLUSION: PAQR3 was significantly down-regulated in GCA tissues, HGC27, and SGC7901 cells. PAQR3 significantly inhibits the proliferation, migration, and invasion of HGC27 cells. Mechanistically, PAQR3 can inhibit the EMT process in HGC27 cells by regulating TGF-ß/Smad signaling pathway.


Asunto(s)
Adenocarcinoma , Infecciones por Helicobacter , Helicobacter pylori , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Neoplasias Gástricas , Adenocarcinoma/patología , Cardias/metabolismo , Cardias/patología , Línea Celular Tumoral , Humanos , Proteínas Smad/metabolismo , Neoplasias Gástricas/patología , Factor de Crecimiento Transformador beta/metabolismo
5.
Nature ; 597(7876): 398-403, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34433965

RESUMEN

Somatic mutations that accumulate in normal tissues are associated with ageing and disease1,2. Here we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies of 9 organs from 5 donors. We found that somatic mutation accumulations and clonal expansions were widespread, although to variable extents, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for in tissues from the oesophagus and cardia. Endogenous mutational processes with the SBS1 and SBS5 mutational signatures are ubiquitous among normal tissues, although they exhibit different relative activities. Exogenous mutational processes operate in multiple tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimetre resolution. In the oesophagus and cardia, macroscopic somatic clones that expanded to hundreds of micrometres were frequently seen, whereas in tissues such as the colon, rectum and duodenum, somatic clones were microscopic in size and evolved independently, possibly restricted by local tissue microstructures. Our study depicts a body map of somatic mutations and clonal expansions from the same individual.


Asunto(s)
Células Clonales/metabolismo , Salud , Mutagénesis , Mutación , Especificidad de Órganos , Anciano de 80 o más Años , Biopsia , Cadáver , Cardias/metabolismo , Proliferación Celular , Células Clonales/citología , Esófago/metabolismo , Femenino , Genómica , Humanos , Masculino
6.
Sci Rep ; 11(1): 4509, 2021 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-33627749

RESUMEN

Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC), but its cellular origin and mechanism of neoplastic progression remain unresolved. Notch signaling, which plays a key role in regulating intestinal stem cell maintenance, has been implicated in a number of cancers. The kinase Dclk1 labels epithelial post-mitotic tuft cells at the squamo-columnar junction (SCJ), and has also been proposed to contribute to epithelial tumor growth. Here, we find that genetic activation of intracellular Notch signaling in epithelial Dclk1-positive tuft cells resulted in the accelerated development of metaplasia and dysplasia in a mouse model of BE (pL2.Dclk1.N2IC mice). In contrast, genetic ablation of Notch receptor 2 in Dclk1-positive cells delayed BE progression (pL2.Dclk1.N2fl mice), and led to increased secretory cell differentiation. The accelerated BE progression in pL2.Dclk1.N2IC mice correlated with changes to the transcriptomic landscape, most notably for the activation of oncogenic, proliferative pathways in BE tissues, in contrast to upregulated Wnt signalling in pL2.Dclk1.N2fl mice. Collectively, our data show that Notch activation in Dclk1-positive tuft cells in the gastric cardia can contribute to BE development.


Asunto(s)
Esófago de Barrett/metabolismo , Quinasas Similares a Doblecortina/metabolismo , Células Epiteliales/metabolismo , Mucosa Gástrica/metabolismo , Metaplasia/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Adenocarcinoma/metabolismo , Animales , Carcinogénesis/metabolismo , Cardias/metabolismo , Diferenciación Celular/fisiología , Proliferación Celular/fisiología , Modelos Animales de Enfermedad , Neoplasias Esofágicas/metabolismo , Esófago/metabolismo , Ratones , Células Madre/metabolismo , Vía de Señalización Wnt/fisiología
8.
J Cell Mol Med ; 24(16): 9457-9465, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32649057

RESUMEN

Gastric cancer (GC) is a heterogeneous tumour with numerous differences of epidemiologic and clinicopathologic features between cardia cancer and non-cardia cancer. However, few studies were performed to construct site-specific GC prognostic models. In this study, we identified site-specific GC transcriptomic prognostic biomarkers using genetic algorithm (GA)-based support vector machine (GA-SVM) and GA-based Cox regression method (GA-Cox) in the Cancer Genome Atlas (TCGA) database. The area under time-dependent receive operating characteristic (ROC) curve (AUC) regarding 5-year survival and concordance index (C-index) was used to evaluate the predictive ability of Cox regression models. Finally, we identified 10 and 13 prognostic biomarkers for cardia cancer and non-cardia cancer, respectively. Compared to traditional models, the addition of these site-specific biomarkers could notably improve the model preference (cardia: AUCtraditional vs AUCcombined  = 0.720 vs 0.899, P = 8.75E-08; non-cardia: AUCtraditional vs AUCcombined  = 0.798 vs 0.994, P = 7.11E-16). The combined nomograms exhibited superior performance in cardia and non-cardia GC survival prediction (C-indexcardia  = 0.816; C-indexnoncardia  = 0.812). We also constructed a user-friendly GC site-specific molecular system (GC-SMS, https://njmu-zhanglab.shinyapps.io/gc_sms/), which is freely available for users. In conclusion, we developed site-specific GC prognostic models for predicting cardia cancer and non-cardia cancer survival, providing more support for the individualized therapy of GC patients.


Asunto(s)
Algoritmos , Biomarcadores de Tumor/genética , Cardias/patología , Regulación Neoplásica de la Expresión Génica , Nomogramas , Neoplasias Gástricas/patología , Transcriptoma , Cardias/metabolismo , Estudios de Casos y Controles , Biología Computacional , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Curva ROC , Neoplasias Gástricas/genética , Tasa de Supervivencia
9.
Eur Rev Med Pharmacol Sci ; 24(1): 428-433, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31957857

RESUMEN

OBJECTIVE: To explore the influences of propofol on the proliferation and apoptosis of cardia cancer cells via mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. PATIENTS AND METHODS: A total of 65 surgical resection specimens of cardia cancer were selected as research objects and divided into control group and with low (12.5 µmol/L), medium (25 µmol/L), and high (50 µmol/L) propofol concentration groups. The apoptosis of cancer cells, ERK1/2 phosphorylation level, expressions of Caspase-3, B-cell lymphoma-2 (Bcl-2), and Bcl-2 associated X protein (Bax) in each group were detected. RESULTS: Propofol in different concentrations could all effectively inhibit the proliferation of cardia cancer cells in a dose-dependent manner. Different concentrations of propofol promoted the apoptosis of cardia cancer cells, and the apoptosis rate constantly increased with the rising concentration of propofol (p<0.05). Propofol could repress the expression of Bcl-2 and up-regulate the expression levels of Caspase-3, Bax, and phosphorylated ERK1/2. CONCLUSIONS: Propofol can inhibit the proliferation and induce the apoptosis of cardia cancer cells, and the action mechanism may be correlated with the inhibition on the MAPK/ERK signaling pathway.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Cardias/efectos de los fármacos , Propofol/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Cardias/metabolismo , Cardias/patología , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología
10.
Gastric Cancer ; 22(4): 705-722, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30656427

RESUMEN

BACKGROUND: Semaphorin 3B (SEMA3B) is frequently inactivated in several carcinomas. However, as the host gene of miR-6872, the roles of SEMA3B, antisense lncRNA SEMA3B-AS1, and miR-6872 in gastric cardia adenocarcinoma (GCA) tumorigenesis have not been clarified. METHODS: The expression levels of SEMA3B, SEMA3B-AS1, and miR-6872 were respectively detected by qRT-PCR, western blot, or immunohistochemical staining assays. The methylation status was determined by BGS and BS-MSP methods. In vitro assays were preformed to explore the biological effects of SEMA3B, SEMA3B-AS1, and miR-6872-5p in gastric cancer cells. Chromatin immunoprecipitation assay was used to detect the binding of protein to DNA. The interaction of SEMA3B-AS1 with MLL4 was identified by RNA immunoprecipitation and RNA pull-down assays. RESULTS: Frequent downregulation of SEMA3B, SEMA3B-AS1, and miR-6872 was detected in GCA tissues and gastric cancer cells. Aberrant hypermethylation of the promoter region was more tumor specific and was negatively correlated with the expression level of SEMA3B, SEMA3B-AS1, and miR-6872-5p. Transcription factor Sp1 activated SEMA3B or SEMA3B-AS1 transcription and CpG sites hypermethylation within promoter region eliminated Sp1 binding ability. Overexpression of SEMA3B and SEMA3B-AS1 inhibited gastric cancer cell proliferation, migration, and invasion in vitro. SEMA3B-AS1 induced the expression of SEMA3B by interacting with MLL4. ZNF143 might be the target gene of miR-6872-5p and miR-6872-5p functioning synergistically with SEMA3B to suppress cell invasion. Furthermore, SEMA3B, SEMA3B-AS1, and miR-6872-5p expression levels were associated with GCA patients' survival. CONCLUSIONS: SEMA3B, SEMA3B-AS1, and miR-6872 may act as tumor suppressors and may serve as potential targets for antitumor therapy.


Asunto(s)
Adenocarcinoma/patología , Cardias/patología , Glicoproteínas de Membrana/genética , MicroARNs/genética , ARN sin Sentido/genética , ARN Largo no Codificante/genética , Semaforinas/genética , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Anciano , Biomarcadores de Tumor/genética , Cardias/metabolismo , Movimiento Celular , Proliferación Celular , Metilación de ADN , Progresión de la Enfermedad , Sinergismo Farmacológico , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Tasa de Supervivencia , Células Tumorales Cultivadas
11.
Nat Commun ; 10(1): 39, 2019 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-30604760

RESUMEN

The human gastric mucosa is the most active layer of the stomach wall, involved in food digestion, metabolic processes and gastric carcinogenesis. Anatomically, the human stomach is divided into seven regions, but the protein basis for cellular specialization is not well understood. Here we present a global analysis of protein profiles of 82 apparently normal mucosa samples obtained from living individuals by endoscopic stomach biopsy. We identify 6,258 high-confidence proteins and estimate the ranges of protein expression in the seven stomach regions, presenting a region-resolved proteome reference map of the near normal, human stomach. Furthermore, we measure mucosa protein profiles of tumor and tumor nearby tissues (TNT) from 58 gastric cancer patients, enabling comparisons between tumor, TNT, and normal tissue. These datasets provide a rich resource for the gastrointestinal tract research community to investigate the molecular basis for region-specific functions in mucosa physiology and pathology including gastric cancer.


Asunto(s)
Mucosa Gástrica/metabolismo , Proteínas de Neoplasias/análisis , Proteoma/análisis , Neoplasias Gástricas/patología , Biopsia , Carcinogénesis/patología , Cardias/metabolismo , Cardias/patología , Conjuntos de Datos como Asunto , Fundus Gástrico/metabolismo , Fundus Gástrico/patología , Mucosa Gástrica/patología , Gastroscopía , Humanos , Proteínas de Neoplasias/metabolismo , Proteoma/metabolismo , Proteómica/métodos , Antro Pilórico/metabolismo , Antro Pilórico/patología , Píloro/metabolismo , Píloro/patología
12.
J Natl Cancer Inst ; 111(1): 34-41, 2019 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29788475

RESUMEN

Background: Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case-control study drawn from participants in three prospective cohort studies. Methods: Using gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided. Results: Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log2 DHEA = 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, Ptrend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed. Conclusions: This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men.


Asunto(s)
Adenocarcinoma/diagnóstico , Cardias/metabolismo , Neoplasias Esofágicas/diagnóstico , Hormonas Esteroides Gonadales/sangre , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/sangre , Anciano , Cardias/patología , Estudios de Casos y Controles , Neoplasias Esofágicas/sangre , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Neoplasias Gástricas/sangre
14.
Mol Carcinog ; 56(8): 1924-1934, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28345805

RESUMEN

Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 which encodes an lncRNA and is downregulated in an expanding list of cancer cell lines and primary human cancers. The miR-770 is transcribed from the intronic sequence of MEG3 and MEG3 may be the host gene for miR-770. However, the biological role of MEG3 and miR-770 in gastric cardia adenocarcinoma (GCA) development and prognosis is poorly defined. The present study was to investigate the function and methylation status of MEG3 in GCA, and further to detect the functional association of miR-770 and its host gene MEG3 in GCA carcinogenesis and prognosis. MEG3 and miR-770 was significantly downregulated in GCA patients and cell lines, and their expression was associated with TNM stage and lymph node metastasis. Overexpression of MEG3 and miR-770 inhibited gastric cancer cell proliferation and invasion in vitro. Furthermore, the expression level of MEG3 and miR-770 was significantly increased in cancer cells after treated with 5-Aza-dC. The aberrant hypermethylation of proximal promoter and enhancer region of MEG3 was detected in GCA tissues. In addition, the proximal promoter and enhancer region hypermethylation and dysregulation of MEG3 and miR-770 were associated with poorer GCA patients' survival. These findings suggest that miR-770 and its host gene MEG3 may play tumor suppressor role and hypermethylation of proximal promoter and enhancer region may be one of the critical mechanisms in inactivation of MEG3 and miR-770 in GCA development. MEG3 and miR-770 may be used as potential biomarkers in predicting GCA patients' prognosis.


Asunto(s)
Adenocarcinoma/genética , Cardias/patología , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Adulto , Anciano , Secuencia de Bases , Cardias/metabolismo , Regulación hacia Abajo , Epigénesis Genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Regiones Promotoras Genéticas , Neoplasias Gástricas/patología
15.
Oncotarget ; 7(34): 54973-54982, 2016 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-27384681

RESUMEN

BACKGROUND: Gastric cardia cancer (GCC) is located in the distal stomach, and strongly correlates with atrophic gastritis and Helicobacter pylori (H.pylori) infection. Caudal-related homeobox transcription factor 2 (CDX2) is homeobox gene encoding an intestine-specific transcription factor usually expressed in the intestinal epithelium cells. However, in several recent published papers, CDX2 was found to be aberrantly expressed in gastric, thyroid and ovarian cancer. RESULTS: Higher expression of CDX2 was found in GCC tissues in comparison with non-malignant cardia mucosa (p<0.05). Moreover, immunohistochemical analysis demonstrated that CDX2 expression correlated with lymphatic metastasis. In addition, we found that CDX2 expression progressively increased with the level of H. pylori infection (p<0.05), and also correlated with cell proliferation, based on Ki67 staining. METHODS: To investigate the relationship between CDX2, cell proliferation and H. pylori infection, we detected CDX2, Ki62 and H.pylori expression in 83 non-malignant gastric cardia mucosacases and 60 GCC specimens in the Chaoshan area, a high-risk region for esophageal and gastric cardia cancer. CONCLUSION: These findings provide pathological evidence that H. pylori infectionis a driving force of gastric cardia carcinogenesis by upregulating CDX2 and inducing inflammation. These results provide new pathological evidence that H. pylori infection induces GCC tumorigenesis.


Asunto(s)
Adenocarcinoma/metabolismo , Factor de Transcripción CDX2/metabolismo , Cardias/metabolismo , Infecciones por Helicobacter/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/microbiología , Adulto , Anciano , Cardias/microbiología , Cardias/patología , Proliferación Celular , Femenino , Gastritis/metabolismo , Gastritis/microbiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/microbiología , Adulto Joven
16.
Oncotarget ; 7(21): 31067-78, 2016 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-27105510

RESUMEN

Gastric cardia adenocarcinoma (GCA) is the most aggressive subtype of gastric cancer with a high metastatic rate. In this report, we collected tumor tissue samples from 214 GCA cases and examined expression of CYR61, a target gene product of the Hippo-YAP/TAZ pathway, in the GCA tumors by immunohistochemical (IHC) staining using the tissue microarray assay (TMA). The results have shown that CYR61 is overexpressed in 44% of the GCA tumor samples. Expression of CYR61 is inversely correlated with cumulative survival of GCA patients (p<0.001) and significantly associated only with metastatic pathological categories (with N category, p=0.052; with TNM stage, p=0.001). Furthermore, knockdown of CYR61 in gastric cancer AGS cells impairs the cancer cell migration and invasion, suggesting a driver role of CYR61 in metastasis. Thus, our studies have established CYR61 as a metastatic biomarker for prediction of poor prognosis of GCA and provided a potential molecular target for anti-metastatic therapy of GCA.


Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Cardias/patología , Proteína 61 Rica en Cisteína/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Cardias/metabolismo , Proteína 61 Rica en Cisteína/genética , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Transfección
17.
Ann Surg Oncol ; 23(3): 943-50, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26530444

RESUMEN

BACKGROUND: The clinical role of microsatellite instability (MSI) in gastric cancer (GC) is controversial. A large series of patients submitted to respective surgery for primary GC with a long follow-up time was evaluated. METHODS: 472 patients with prospectively collected frozen samples of normal mucosa and tumor tissue stored in a biological tissue bank were included. Microsatellite analysis was evaluated using 5 quasi monomorphic mononucleotide repeats (BAT-26, BAT-25, NR-24, NR-21, and NR-27). The presence of MSI in 2 or more loci was classified as MSI-H, whereas all other cases were included in the microsatellite-stable (MSS) group. RESULTS: MSI-H phenotype was found in 111 of 472 patients (23.5%). MSI-H status was related significantly with older age, female gender, non-cardia location, WHO histotype, non-cardia Lauren intestinal type, and less advanced stages. Cancer-related 5-year survival was significantly higher in MSI-H versus MSS group (67.6% vs. 35%, p < 0.001). Stratified analysis revealed a significant impact of MSI on prognosis in non-cardia tumors of intestinal type or tubular/poorly differentiated histology, particularly in stages II and III; multivariate Cox regression analysis confirmed MSS status as a strong predictor of poor prognosis (hazard ratio 2.65, 95% CI 1.56-4.51, p < 0.001) in non-cardia intestinal type. No prognostic value of MSI in the diffuse-mixed type and signet-ring cell/mucinous histotypes was observed. CONCLUSIONS: MSI was confirmed as a significant predictor of long term outcome in a large series of GC with a long follow-up time, but the prognostic value is limited to selected histotypes of non-cardia tumors.


Asunto(s)
Adenocarcinoma/secundario , Carcinoma Papilar/secundario , Carcinoma de Células en Anillo de Sello/secundario , Cardias/patología , Neoplasias Intestinales/patología , Inestabilidad de Microsatélites , Neoplasias Gástricas/patología , Adenocarcinoma/genética , Adenocarcinoma/cirugía , Anciano , Carcinoma Papilar/genética , Carcinoma Papilar/cirugía , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/cirugía , Cardias/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Gastrectomía , Humanos , Neoplasias Intestinales/genética , Neoplasias Intestinales/cirugía , Escisión del Ganglio Linfático , Metástasis Linfática , Masculino , Invasividad Neoplásica , Estadificación de Neoplasias , Fenotipo , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Prospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/cirugía , Tasa de Supervivencia
18.
Proc Natl Acad Sci U S A ; 112(8): E852-61, 2015 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-25675536

RESUMEN

"Regulatory evolution," that is, changes in a gene's expression pattern through changes at its regulatory sequence, rather than changes at the coding sequence of the gene or changes of the upstream transcription factors, has been increasingly recognized as a pervasive evolution mechanism. Many somatic sexually dimorphic features of Drosophila melanogaster are the results of gene expression regulated by the doublesex (dsx) gene, which encodes sex-specific transcription factors (DSX(F) in females and DSX(M) in males). Rapid changes in such sexually dimorphic features are likely a result of changes at the regulatory sequence of the target genes. We focused on the Flavin-containing monooxygenase-2 (Fmo-2) gene, a likely direct dsx target, to elucidate how sexually dimorphic expression and its evolution are brought about. We found that dsx is deployed to regulate the Fmo-2 transcription both in the midgut and in fat body cells of the spermatheca (a female-specific tissue), through a canonical DSX-binding site in the Fmo-2 regulatory sequence. In the melanogaster group, Fmo-2 transcription in the midgut has evolved rapidly, in contrast to the conserved spermathecal transcription. We identified two cis-regulatory modules (CRM-p and CRM-d) that direct sexually monomorphic or dimorphic Fmo-2 transcription, respectively, in the midguts of these species. Changes of Fmo-2 transcription in the midgut from sexually dimorphic to sexually monomorphic in some species are caused by the loss of CRM-d function, but not the loss of the canonical DSX-binding site. Thus, conferring transcriptional regulation on a CRM level allows the regulation to evolve rapidly in one tissue while evading evolutionary constraints posed by other tissues.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Evolución Molecular , Genes de Insecto , Pleiotropía Genética , Caracteres Sexuales , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Secuencia de Bases , Sitios de Unión/genética , Cardias/metabolismo , Proteínas de Drosophila/metabolismo , Cuerpo Adiposo/citología , Cuerpo Adiposo/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Modelos Biológicos , Datos de Secuencia Molecular , Unión Proteica , Secuencias Reguladoras de Ácidos Nucleicos/genética , Especificidad de la Especie , Transcripción Genética
19.
Hepatogastroenterology ; 61(134): 1835-42, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25436388

RESUMEN

BACKGROUND/AIMS: : This study aims to comparing the gene expression profiles and molecular interactions among gastric cardiac adenocarcinomas (GCA), gastric noncardiac adenocarcinomas (GNCA) and their adjacent normal tissues. METHODOLOGY: Gene expression profile of GSE29272 was downloaded from Gene expression omnibus. Differentially expressed genes (DEGs) were identified at the cut-off of p-value ≤ 0.01. Gene ontology (GO) enrichment analysis was further performed for the DEGs, and then the binding sites of the transcriptional factors and the specific protein-protein interactions were analyzed. RESULTS: Total 1024 DEGs were screened, including 741 up-regulated genes and 283 down-regulated genes. VSNL1 (visinin-like protein-1) is expressed relatively higher in the GNCA and could be its molecular biomarker, as KRT14 (cytokeratin 14) in the GCA. GO analysis showed that the analogous cancer-relevant factors network appears in these two cancer subgroups. The DEGs in the GCA tend to be bound by SPIB and ZNF354C. FN1 lies in the center of the protein-protein interaction networks of the two cancer subgroups. CONCLUSIONS: We found out the RNA expression level of the two gastric cancers varied greatly from the normal tissues while gene expression profile of them were very similar, however, the different biomarker and transcriptional factors indicate the differences of two mechanisms.


Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Cardias , Regulación Neoplásica de la Expresión Génica , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Sitios de Unión , Biomarcadores de Tumor/metabolismo , Cardias/metabolismo , Cardias/patología , Biología Computacional , Bases de Datos Genéticas , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Mapas de Interacción de Proteínas , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
20.
Br J Biomed Sci ; 71(2): 86-92, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24974686

RESUMEN

Interest has increased in CDX2 gene expression in oesophageal non-goblet-cell columnar metaplasia as recent investigations indicate such metaplasia possesses neoplastic potential. This study aims to assess expression of the transcription factor CDX2 specifically in non-goblet-cell cardia and fundic oesophageal metaplastic tissue, and to compare the location of CDX2 expression in non-goblet-cell specimens to that in goblet-cell specimens. A total of 43 patient specimens (20 fundic-type metaplasia, 42 cardia-type metaplasia and 18 intestinal metaplasia goblet cell-positive) were examined in this study. These were selected over six months from a patient database using the systematised nomenclature of human and veterinary medicine coding system (SNOMED). CDX2 was detected in patient specimens with an anti-CDX2 mouse monoclonal antibody. The types of mucosa in each specimen were confirmed by haematoxylin and eosin (H&E) staining. Fundic specimens were consistently CDX2-negative (0%). CDX2 expression was distinct in 55% of cardia and 100% of intestinal cases. Nearly all cardia-positive cases displayed focal expression (95.5%) and all intestinal cases displayed diffuse distribution of expression. Almost all cardia- and intestinal-positive specimens demonstrated epithelial expression (95.5% and 100%, respectively). The percentage of cardia-positive specimens with deep tissue expression was lower than in intestinal specimens (31.8% vs. 94.4%, respectively). This study confirms CDX2 as an early marker for Barrett's oesophagus in the absence of goblet cells as expression was noted in cardia metaplasia. CDX2 appears to induce the transformation of the normal oesophageal mucosa to cardia type, which then differentiates to an intestinal type under the influence of gastro-oesophageal reflux disease.


Asunto(s)
Esófago de Barrett/metabolismo , Proteínas de Homeodominio/metabolismo , Esófago de Barrett/patología , Biomarcadores/metabolismo , Factor de Transcripción CDX2 , Cardias/metabolismo , Cardias/patología , Diferenciación Celular , Humanos , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Microscopía de Polarización , Proteínas Supresoras de Tumor/metabolismo
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