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1.
PLoS One ; 15(10): e0238836, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095797

RESUMO

Recently, the Cancer Genome Atlas and Asian Cancer Research Group propose two new classifications system of gastric cancer by using multi-platforms of molecular analyses. However, these highly complicated and cost technologies have not yet been translated into full clinical utility. In addition, the clinicians are expected to gain more guidance of treatment for different molecular subtypes. In this study, we developed a panel of gastric cancer patients in population from Southern China using commercially accessible TMA and immunohistochemical technology. A cohort of 259 GC patients was classified into 4 subtypes on the basis of expression of mismatch repair proteins (PMS2, MLH1, MSH2, and MSH6), E-cadherin and p21 protein. We observed that the subtypes presented distinct prognosis. dMMR-like subtype was associated with the best prognosis, and E-cadherin-a subtype was associated with the worst prognosis. Patients with p21-High and p21-Ligh subtypes had intermediate overall survival. In multivariate analysis, the dMMR-like subtype remained an independent prediction power for overall survival in the model. We described a molecular classification of gastric cancers using clinically applicable assay. The biological relevance of the four subtypes was illustrated by significant differences in prognosis. Our molecular classification provided an effective and inexpensive screening tool for improving prognostic models. Nevertheless, our study should be considered preliminary and carries a limited predictive value as a single-center retrospective study.


Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/classificação , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , China , Estudos de Coortes , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Análise Serial de Tecidos
2.
Medicine (Baltimore) ; 99(41): e22271, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031269

RESUMO

BACKGROUND: This study will summarize the clinical significance of E-Cadherin and ß-catenin in early gastric cancer (EGC). METHODS: Eligible case-control studies were searched from Cochrane Library, PUBMED, EMBASE, PsycINFO, Google Scholar, CBM, and CNKI from inception to the present. In addition, we will also search other sources to avoid missing potential studies. Two authors will independently carry out study selection, data collection, and study methodological quality. A fixed or random-effects model will be utilize to synthesize the data, and RevMan 5.3 software will be used for data analysis. RESULTS: This study will summarize all eligible studies to investigate the clinical significance of E-Cadherin and ß-catenin in EGC. CONCLUSION: The findings of this study may present a genuine understanding of perspective on the clinical significance of E-Cadherin and ß-catenin in EGC.


Assuntos
Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Projetos de Pesquisa , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Humanos , Revisões Sistemáticas como Assunto
3.
Zhonghua Zhong Liu Za Zhi ; 42(8): 648-652, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867456

RESUMO

Objective: To investigate the relationship between KDM6A mutation or expression and clinicopathological characteristics of gastric cancer. Methods: Fifty-seven cases of gastric cancer tissues were analyzed by second-generation sequencing, and bioinformation database such as Cbioportal, Kaplan Meier-Plotter, and the Human Protein Atlas were used to analyze the relationship between KDM6A mutation and clinicopathological characteristics of gastric cancer. Results: Among 57 gastric cancer samples, 14 were KDM6A mutation, and the mutation proportion was 24.6%. Compared with the non-mutation group, the Borrmann classification, T stage, TNM stage and tumor diameter of KDM6A mutant group were significantly different (all P<0.05). The median survival time of the KDM6A mutant patients was 53.5 months, significantly shorter than 72.0 months of the KDM6A non-mutation patients (P=0.007). The analysis result of Kaplan Meier-Plotter database showed that, among all of the 875 patients, 655 patients had low KDM6A expression and 220 patients had high expression. The median survival time of patients with low expression was 23.5 months, significantly shorter than 30.8 months of patients with high expression (P=0.002). In male, gastric cancer patients with stage Ⅲ, intestinal type, diffuse type, simple surgical treatment and fluorouracil chemotherapy, the expression of KDM6A is related to the patient's overall survival time (all P<0.05). The analysis result of Cbioportal database showed that, among all of the 1 172 gastric cancer patients, 70 patients with KDM6A mutation, 1100 patients with non-mutation. The median overall survival time of mutant patients was 28.9 months, significantly shorter than 35.9 months of non-mutation patients (P<0.001). The analysis result of Human Protein Atlas database showed that, among all of the 355 gastric cancer patients, 97 patients had high KDM6A expression and 258 patients had low KDM6A expression. The median survival time of patients with low expression was 13.7 months, significantly shorter than 19.8 months of patients with high expression (P=0.022). Conclusions: The survival time of gastric cancer patients with KDM6A mutation or low expression is shorter. The mutation and expression of KDM6A are related to clinical pathological factors, which may become a potential target for the diagnosis and treatment of gastric cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Histona Desmetilases/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Histona Desmetilases/genética , Humanos , Metástase Linfática , Masculino , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida
4.
Yonsei Med J ; 61(9): 750-761, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32882759

RESUMO

PURPOSE: Gastric cancer (GC) is a malignant tumor with a high mortality rate. Drug resistance is a major obstacle to GC therapy. This study aimed to investigate the role and mechanism of exosomal circPRRX1 in doxorubicin resistance in GC. MATERIALS AND METHODS: HGC-27 and AGS cells were exposed to different doses of doxorubicin to construct doxorubicin-resistant cell lines. Levels of circPRRX1, miR-3064-5p, and nonreceptor tyrosine phosphatase 14 (PTPN14) were detected by quantitative real-time PCR or Western blot assay. Then, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, transwell, and Western blot assays were used to explore the function of circPRRX1 in GC cells. Interactions among circPRRX1, miR-3064-5p, and PTPN14 were confirmed by dual-luciferase reporter assay. The in vivo function of circPRRX1 was analyzed in a xenograft tumor model. RESULTS: CircPRRX1 was highly expressed in doxorubicin-resistant GC cell lines. Knockdown of circPRRX1 reversed doxorubicin resistance in doxorubicin-resistant GC cells. Additionally, extracellular circPRRX1 was carried by exosomes to spread doxorubicin resistance. CircPRRX1 silencing reduced doxorubicin resistance by targeting miR-3064-5p or regulating PTPN14. In GC patients, high levels of circPRRX1 in serum exosomes were associated with poor responses to doxorubicin treatment. Moreover, depletion of circPRRX1 reduced doxorubicin resistance in vivo. CONCLUSION: CircPRRX1 strengthened doxorubicin resistance by modulating miR-3064-5p/PTPN14 signaling and might be a therapeutic target for GC patients.


Assuntos
Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio , Humanos , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
5.
PLoS One ; 15(9): e0238379, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915799

RESUMO

BACKGROUND: The correlation between the infection of H. pylori and the occurrence of gastric MALT lymphoma (GML) has been well documented. However, the mechanism of how GML is caused by this bacterium is not well understood, although some immunologic mechanisms are thought to be involved. MATERIALS AND METHODS: In this study, we performed both transcriptomic and proteomic analyses on gastric cancer cells infected by H. pylori isolates from GML patients and the gastric ulcer strain 26695 to investigate the differentially expressed molecular signatures that were induced by GML isolates. RESULTS: Transcriptomic analyses revealed that the differentially expressed genes (DEGs) were mainly related to binding, catalytic activity, signal transducer activity, molecular transducer activity, nucleic acid binding transcription factor activity, and molecular function regulator. Fifteen pathways, including the Wnt signaling pathway, the mTOR signaling pathway, the NOD-like receptor signaling pathway and the Hippo signaling pathway, were revealed to be related to GML isolates. Proteomic analyses results showed that there were 116 differentially expressed proteins (DEPs). Most of these DEPs were associated with cancer, and 29 have been used as biomarkers for cancer diagnosis. We also found 63 upstream regulators that can inhibit or activate the expression of the DEPs. Combining the proteomic and transcriptomic analyses revealed 12 common pathways. This study provides novel insights into H. pylori-associated GML. The DEPs we found may be good candidates for GML diagnosis and treatment. CONCLUSIONS: This study revealed specific pathways related to GML and potential biomarkers for GML diagnosis.


Assuntos
Biomarcadores/análise , Infecções por Helicobacter/complicações , Helicobacter pylori/isolamento & purificação , Linfoma de Zona Marginal Tipo Células B/epidemiologia , Proteoma/análise , Neoplasias Gástricas/epidemiologia , Transcriptoma , China/epidemiologia , Perfilação da Expressão Gênica , Infecções por Helicobacter/microbiologia , Humanos , Incidência , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/microbiologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Via de Sinalização Wnt
6.
Medicine (Baltimore) ; 99(36): e21883, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899018

RESUMO

To investigate the expression and clinical significance of aquaporin-1 (AQP1), vascular endothelial growth factor (VEGF) and microvessel density (MVD) in gastric cancer.A total of 79 gastric cancer patients who were admitted into Beijing Chao-Yang Hospital from January, 2018 to December, 2019 were involved in this study. Tumor specimens and para-cancerous normal tissues (> 2 cm away from the tumor) of all the enrolled patients were collected. Immunohistochemistry were performed to identify the expression of AQP1, VEGF, and MVD and the correlation between AQP1, VEGF, MVD, and clinicopathological parameters was analyzed.The expression of AQP1, VEGF and MVD in gastric cancer tissue was increased significantly compared with those in para-cancerous tissue (P < .05). AQP1, VEGF, and MVD were closely correlated with gastric cancer differentiation, lymph node metastasis, vascular tumor thrombosis and clinical stage (P < .05). Spearman correlation analysis showed that AQP1 was positively associated with VEGF expression (r = 0.497, P < .05). MVD was enhanced in VEGF or AQP1 positive cancer tissues compared with that in VEGF or AQP1 negative tissue (P < .05).Synergistic effect among AQP1, VEGF, and MVD is involved in occurrence and development of gastric cancer.


Assuntos
Aquaporina 1/metabolismo , Microvasos/patologia , Neoplasias Gástricas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
7.
Proc Natl Acad Sci U S A ; 117(36): 22390-22401, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32848063

RESUMO

Targeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, have emerged as promising candidates for targeted cancer therapy. PPD proteins are essential for small noncoding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out the PIWIL1 gene (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that KO significantly changes the transcriptome, causing the up-regulation of most of its associated transcripts. Surprisingly, few bona fide piRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a piRNA-independent function of PIWIL1 in promoting gastric cancer.


Assuntos
Proteínas Argonauta , RNA Interferente Pequeno , Neoplasias Gástricas , Animais , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Linhagem Celular Tumoral , Feminino , Técnicas de Inativação de Genes , Humanos , Masculino , Camundongos , Camundongos Nus , Degradação do RNAm Mediada por Códon sem Sentido/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Estômago/química , Estômago/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
8.
Medicine (Baltimore) ; 99(32): e21138, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769866

RESUMO

BACKGROUND: The high morbidity and mortality of Gastric cancer (GC) is seriously endangered human health. Owing to the low rate of early diagnosis and human body can resistant to the anti-tumor drugs, so an early diagnostic biology marker is essential. However, recently studies indicated that Mammalian target of rapamycin (mTOR) is usually frequently deregulated in many cancers, especially in GC. And the efficacy of mTOR inhibitor was promising in a phase II clinical trial which could inhibited the proliferation of GC cells and delayed tumor progression. Therefore, mTOR were identified as a potential prognosis biomarker for GC, and its inhibitor will be promising in anti-GC therapy. The main aim of this systematic review and meta-analysis is to investigate the relationships between the expression level and prognostic value of mTOR in patients with GC. METHODS: Four electronic databases were systematically searched as follow: the PubMed, EMbase, Web of Science databases, and the Cochrane Library. All the data will be extracted by independent researchers from the eligible studies with the inclusion and exclusion criteria. And the data will be analyzed through STATA 12.0 software. RESULTS AND CONCLUSION: This meta-analysis indicated that overexpressed mTOR was significantly in predicting a poorer prognosis for GC patients. The expression level of mTOR should be considered as a potential independent prognostic predictor for GC patients. PROTOCOL REGISTRATION NUMBER: CRD42020159690.


Assuntos
Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Biomarcadores/metabolismo , Humanos , Prognóstico
9.
Gene ; 762: 145044, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32777528

RESUMO

OBJECTIVE: Gastric cancer is the most common malignant tumor. Most patients suffering from gastric cancer die of metastasis. The role of Atrial natriuretic peptide (ANP) in inhibiting and eliminating kinds of cancer cells has been reported. Aberrant activation of Hedgehog (Hh) signaling pathway contributes to initiation and progression of various malignancies. We have previously reported that the inhibitor of Hh, cyclopamine, reduces the metastatic activity of MGC-803 via inhibiting the expression of matrix metalloproteinases (MMP)-9. It remains to be further demonstrated that ANP has the suppressive effects on invasion and metastasis in gastric cancer via Hh-mediated MMP-9 production. METHODS: Transwell, western blot, qRT-PCR were used after application of ANP on MGC-803 gastric cancer cells to determine the levels of cell migration and invasion, protein levels of MMP-9 and Hh, as well as mRNAs of MMP-9 and Hh, respectively. RESULTS: It was demonstrated that the migration and invasion were significantly lower, MMP-9 and Hh as well as their mRNAs were lower as well, in ANP-treated MGC-803 gastric cancer cells than those in control. CONCLUSIONS: The expression of MMP-9 induced by aberrant activation of Hh in MGC-803 was inhibited by ANP, which may contribute to the inhibition of cell migration and invasion. These results suggested the potential of ANP to be used in gastric cancer therapy as an inhibitor targetting Hh signaling pathway to inhibit the proliferation as well as invasion and metastasis of gastric cancer.


Assuntos
Fator Natriurético Atrial/farmacologia , Proteínas Hedgehog/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Neoplasias Gástricas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Metaloproteinase 9 da Matriz/genética , Transdução de Sinais/efeitos dos fármacos
10.
PLoS One ; 15(8): e0236811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745141

RESUMO

In this study, we aimed to investigate the molecular biomarkers that are pivotal for the development and progression of gastric cancer (GC). We analyzed clinical specimens using RNA sequencing to identify the target genes. We found that the expression of HOXC6 mRNA was upregulated with the progression of cancer, which was validated by quantitative real time PCR and RNA in-situ hybridization. To compare the protein expression of HOXC6, we evaluated GC and normal gastric tissue samples using western blot analysis and immunohistochemistry. We detected significantly higher levels of HOXC6 in the GC tissues than in the normal controls at both mRNA and protein levels. The expression levels of HOXC6 mRNA in patients with advanced gastric cancer (AGC) were significantly higher than those in patients with early gastric cancer (EGC). Kaplan-Meier curves showed that high expression of HOXC6 mRNA is significantly associated with poor clinical prognosis. Our findings suggest that HOXC6 mRNA may be a novel biomarker and can be potentially valuable in predicting the prognosis of GC patients. Especially, HOXC6 mRNA in-situ hybridization may be a diagnostic tool for predicting prognosis of individual GC patients.


Assuntos
Proteínas de Homeodomínio , Neoplasias Gástricas , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/secundário
11.
PLoS Pathog ; 16(8): e1008778, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841292

RESUMO

EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.


Assuntos
Biomarcadores/metabolismo , Epigênese Genética , Gammaherpesvirinae/isolamento & purificação , Regulação Viral da Expressão Gênica , Infecções por Herpesviridae/complicações , Interações Hospedeiro-Patógeno , Neoplasias Gástricas/genética , Biomarcadores/análise , Metilação de DNA , Gammaherpesvirinae/genética , Células HEK293 , Infecções por Herpesviridae/virologia , Proteínas Homeobox A10/genética , Humanos , Incidência , Metalotioneína/genética , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/virologia , Ativação Viral , Replicação Viral
12.
Anticancer Res ; 40(8): 4537-4545, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727784

RESUMO

BACKGROUND/AIM: Altered connexin expression has been associated with cancer development and progression. This study evaluated connexin 26, 32, and 43 expression in association with the long-term outcomes of gastric cancer after gastrectomy. PATIENTS AND METHODS: Pathological specimens were collected from 113 patients who underwent gastrectomy for gastric cancer, of whom 104 were included in the study. The expression levels of the connexins were assessed by immunohistochemistry. The patients were classified into low and high groups according to the median histoscore of connexin. RESULTS: Cancer-specific survival (CSS) was significantly longer in the high than low connexin 43 group (p=0.030), particularly in patients >65 years old (p=0.030). A multivariate analysis identified pathological stage, differentiation type, and connexin 43 expression as possible predictors of CSS in patients (difference in the area under the curve=0.232, 0.090, and 0.094). CONCLUSION: Low connexin 43 expression predicted a poor CSS in gastric cancer patients after gastrectomy.


Assuntos
Conexina 43/metabolismo , Conexinas/metabolismo , Neoplasias Gástricas/cirurgia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo , Feminino , Gastrectomia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento
13.
Gene ; 757: 144937, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32640300

RESUMO

MicroRNAs (miRNAs) are a group of non-coding RNAs that have critical roles in regulation of expression of genes. They can inhibit or decrease expression of target genes mostly via interaction with 3' untranslated region of their targets. Their crucial roles in the regulation of expression of tumor suppressor genes and oncogenes have potentiated them as contributors in tumorigenesis. Moreover, their stability in body fluids has enhanced their potential as cancer biomarkers. In the present review article, we describe the role of miRNAs in the pathogenesis of gastric cancer and advances in application of miRNAs as biomarkers and therapeutic targets in this kind of malignancy.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Gástricas/genética , Animais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , MicroRNAs/sangue , MicroRNAs/metabolismo , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo
14.
Rev Assoc Med Bras (1992) ; 66(5): 590-595, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32638965

RESUMO

OBJECTIVE Thrombopoietin (THPO) is well-known as a megakaryocyte growth and development factor (MGDF) involved in megakaryocyte proliferation and maturation. To explore the biological effects of THPO in gastric adenocarcinoma, we conducted this study. Methods: By accessing the TCGA database, the expression level of THPO was determined in tumor tissues. The association between THPO expression and clinical features, or prognostic significance was described by Cox regression analysis and Kaplan-Meier. The SiRNA method was used to decline the THPO expression; then cell viability, invasion, and migration were detected to verify the effects of the knockdown of THPO. qPCR and western blotting were implemented to examine the expression level of THPO. Results: The expression of THPO was increased in tumor tissue and cells, its high-regulation was associated with a poor prognosis in patients with gastric adenocarcinoma. Cell viability, invasion, and migration were suppressed in AGS with the down-regulation of THPO. Furthermore, on the basis of si-THPO transfection, E-cadherin was promoted while N-cadherin and Vimentin were attenuated. CONCLUSION Our results revealed that THPO may be a potent marker of gastric adenocarcinoma, providing a novel potential screening method for gastric adenocarcinoma.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias Gástricas/diagnóstico , Trombopoetina/metabolismo , Adenocarcinoma/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica , Prognóstico , Neoplasias Gástricas/metabolismo
15.
Int J Exp Pathol ; 101(3-4): 96-105, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32608553

RESUMO

Long non-coding RNAs (lncRNAs) have been proven to play important roles in various cancers, including gastric cancer (GC). However, detailed knowledge about lncRNAs in GC is limited. Therefore we carried out an in-depth study of public data and found 83 differently expressed lncRNAs in GC. To further confirm the target genes of these lncRNAs, we constructed a co-expression network between lncRNAs and mRNAs and found three lncRNAs (MBNL1-AS1, HAND2-AS1 and MIR100HG) were at the core of the network. By coalition analysis of clinical information and the three lncRNAs' expression level from The Cancer Genome Atlas (TCGA) and GSE15459 data sets, we found MIR100HG could be a potential prognostic factor. Clinical samples showed patients with higher MIR100HG expression had poorer prognosis, and further experiments demonstrated that MIR100HG was associated with proliferation, migration and invasion of GC cells. Hopefully, MIR100HG might be considered as a novel prognostic factor and biomarker for GC.


Assuntos
Biologia Computacional , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
16.
Chem Biol Interact ; 328: 109196, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32687844

RESUMO

Cancer metastasis and resistance for chemotherapeutic agent correlate with epithelial-mesenchymal transition (EMT), while ROS production also involves in the EMT process, However, how autophagy mediated ROS production affects EMT remains unclear. Previous study showed that DpdtC (2,2'-di-pyridylketone hydrazone dithiocarbamate) could induce ferritinophagy in HepG2 cell. To insight into more details that how ferritinophagy affects cellular feature, the SGC-7901and BGC-823 gastric cancer cell lines were used. Interestingly DpdtC treatment resulted in EMT inhibition and was ROS dependent. Similar situation occurred in TGF-ß1 induced EMT model, supporting that DpdtC was able to inhibit EMT. Next the ability of DpdtC in ferritinophagy induction was further evaluated. As expected, DpdtC induced ferritinophagy in the absence and presence of TGF-ß1. The correlation analysis revealed that an enhanced ferritinophagic flux contributed to the EMT inhibition. In addition, ferritinophagy triggers Fenton reaction, resulting in ROS production which give rise of p53 response, thus the role of p53 was further investigated. DpdtC treatment resulted in upregulation of p53, but, the addition of p53 inhibitor, PFT-α could significantly neutralize the action of DpdtC on ferritinophagy induction and EMT inhibition. Furthermore, autophagy inhibitors or NAC could counteract the action of DpdtC, indicating that ferrtinophagy-mediated ROS played an important role in the cellular events. In addition to upregulation of p53, its down-stream targets, AKT/mTor were also downregulated, supporting that DpdtC induced EMT inhibition was achieved through ferritinophagy-ROS vicious cycle mediated p53/AKT/mTor pathway. And the activation of ferritinophagic flux was the dominant driving force in action of DpdtC in gastric cancer cells.


Assuntos
Autofagia , Transição Epitelial-Mesenquimal , Ferritinas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/patologia , Serina-Treonina Quinases TOR/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Ditiocarb/análogos & derivados , Ditiocarb/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Fator de Crescimento Transformador beta1/farmacologia
17.
Acta Gastroenterol Belg ; 83(2): 249-254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603043

RESUMO

Introduction: We studied the relation between premalignant gastric lesions and cyclooxygenase-2 (COX-2) expression. Methods: The study included 254 patients, who were histo- logically diagnosed with chronic active gastritis, atrophy, dys- plasia and metaplasia. Gastric biopsy specimens of the patients were histopathologically examined in terms of the presence of Helicobacter pylori (H. pylori) infection, atrophy The Operative Link for Gastritis Assessment ; (OLGA staging system), dysplasia (Vienna classification), and metaplasia (Sydney classification). COX-2 expression was investigated by immunohistochemical staining. COX-2 immunoreactivity score was calculated as the product of staining intensity and staining area. A score of >1 was defined as COX-2-positive expression. Results: Of these patients, 84 (33.1%) had negative COX-2 expression (Score 0 and Score 1) and 170 (66.9%) had positive COX2 expression (Score 2 and Score 3). We found that in patients with a moderate-marked metaplasia, or with moderate-severe atrophy, a higher OLGA stage, or with dysplasia, the COX-2 expression was found to be higher than those with mild lesions. In 59.8% of the patients H. pylori was positive. While, the rate of severe atrophy was higher in H. pylori-positive patients ; no significant difference was determined between the H. pylori-positive and H. pylori-negative patients regarding age, smoking status, intestinal metaplasia grade, dysplasia, and COX-2 expression. Conclusion: We found a relation between the level of COX-2 expression and the grade of premalignant gastric lesions. COX-2 plays an important role in the gradual process resulting eventually in gastric cancer.


Assuntos
Ciclo-Oxigenase 2 , Gastrite , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Ciclo-Oxigenase 2/metabolismo , Mucosa Gástrica , Humanos , Metaplasia , Neoplasias Gástricas/metabolismo
18.
Life Sci ; 257: 118133, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710946

RESUMO

AIMS: MiR-135b is a downstream effector of oncogenic signaling pathways. This study aimed to reveal the underlying regulation and significance of miR-135b in gastric cancer. MATERIALS AND METHODS: The influence of Wnt and PI3K/AKT signaling pathways on the transcriptional activation of the miR-135b promoter was determined by dual-luciferase reporter assays. In vitro experiments, including the cell counting kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry analysis and malignant phenotype profiles, were conducted to determine the oncogenic role of miR-135b in gastric cancer. To analyze the clinical significance of miR-135b in gastric cancer, the expression profile of miR-135b in tissue specimens and plasma was examined by quantitative real-time PCR (qRT-PCR). KEY FINDINGS: Oncogenic signaling pathways represented by Wnt and PI3K/AKT promoted the transcriptional activation of the miR-135b promoter in gastric cancer. Downregulation of miR-135b inhibited proliferation, promoted apoptosis, and suppressed the migratory, invasive, and adherent abilities as well as the cancer stem cell phenotype of gastric cancer cells. High expression of miR-135b in gastric cancer tissues was tightly associated with poor prognosis and malignant transformation represented by metastasis of gastric cancer. The miR-135b level in the plasma of gastric cancer patients was significantly higher than that in healthy individuals. SIGNIFICANCE: MiR-135b is a potential downstream effector of the Wnt and PI3K/AKT signaling pathways in gastric cancer. High expression of miR-135b may predict malignant transformation and poor prognosis of gastric cancer. This study reveals the potential role of miR-135b as a target for the early diagnosis and therapy of gastric cancer.


Assuntos
Transformação Celular Neoplásica/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Apoptose , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Via de Sinalização Wnt
19.
Anticancer Res ; 40(6): 3255-3264, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487620

RESUMO

BACKGROUND/AIM: Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6. MATERIALS AND METHODS: Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed. RESULTS: In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway. CONCLUSION: Rta contributes to progression of NPC cells through induction of IL-6 in vitro.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neoplasias/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/virologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Transativadores/genética , Fator de Transcrição AP-1/metabolismo , Transfecção , Regulação para Cima
20.
Medicine (Baltimore) ; 99(26): e20635, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590738

RESUMO

BACKGROUND: Gastric cancer (GC) is the most prevailing digestive tract malignant tumor worldwide with high mortality and recurrence rates. However, its potential molecular mechanism and prognostic biomarkers are still not fully understood. We aim to screen novel prognostic biomarkers related to GC prognosis using comprehensive bioinformatic tools. METHODS: Four gene expression microarray data were downloaded from the Gene Expression Omnibus (GEO) database (GSE26942, GSE33335, GSE63089, and GSE79973). Differentially expressed genes (DEGs) between gastric carcinoma and normal gastric tissue samples were identified by an integrated bioinformatic analysis. Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using statistical software R. STRING and Cytoscape software were employed to construct protein-protein interaction (PPI) networks. Hub genes with a high score of connectivity identified from the PPI network were identified. Prognostic values of hub genes were evaluated in GSE15459 dataset. Hub genes related to GC overall survival were further validated in GEPIA (Gene Expression Profiling Interactive Analysis) online tool. RESULTS: A total of 12 upregulated DEGs and 59 downregulated DEGs were identified when the 4 microarray data overlapped. Among them, 10 hub genes with a high score of connectivity were identified. High expression of ghrelin and obestatin prepropeptide (GHRL), BGN, TIMP metallopeptidase inhibitor 1, thrombospondin 2, secreted phosphoprotein 1, and low expression of CHGA were associated with a poor overall survival of gastric cancer (all log rank P < .05). After validation in GEPIA database, only GHRL was confirmed associated with a poor overall survival of gastric cancer (log rank P = .04). CONCLUSIONS: GHRL could be used as a novel biomarker for the prediction of a poor overall survival of gastric cancer, and could be a novel therapeutic target for gastric cancer treatment. However, future experimental studies are still required to validate these findings.


Assuntos
Grelina/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Cromogranina A/metabolismo , Expressão Gênica , Humanos , Análise em Microsséries , Osteopontina/metabolismo , Prognóstico , Trombospondinas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
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