RESUMO
BACKGROUND & AIMS: The association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism. METHODS: C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. RESULTS: Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. CONCLUSIONS: Our study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.
Assuntos
Senescência Celular/imunologia , Gastrite Atrófica/imunologia , Infecções por Helicobacter/imunologia , Lesões Pré-Cancerosas/imunologia , Receptores de Interleucina-8B/metabolismo , Animais , Linhagem Celular , Senescência Celular/efeitos dos fármacos , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite Atrófica/microbiologia , Gastrite Atrófica/patologia , Gastrite Atrófica/prevenção & controle , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/prevenção & controle , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/genética , Transdução de Sinais/imunologiaRESUMO
Aim: To elucidate the clinicopathological significance and prognostic value of SLC17A9 expression in gastric carcinoma (GC). Methods: SLC17A9 mRNA level and its relationship with TP53 mutation was analyzed. SLC17A9 protein expression was examined by immunohistochemistry in 161 patients. Results: SLC17A9 mRNA and protein expression were higher in GC tissues than in adjacent normal tissues (p < 0.01). SLC17A9 mRNA expression was higher in GC tissues having mutated TP53 than in tissues with wild-type TP53 (p < 0.001). High SLC17A9 expression was also significantly associated with poor overall survival and recurrence-free survival and was also found to be an independent prognostic factor for long-term survival in GC patients.Conclusion: Our results show that SLC17A9 may serve as a potential prognostic biomarker in GC patients.
Assuntos
Proteínas de Transporte de Nucleotídeos/biossíntese , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Biomarcadores Tumorais/biossíntese , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/metabolismo , Carcinoma de Células em Anel de Sinete/mortalidade , Carcinoma de Células em Anel de Sinete/patologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Proteínas de Transporte de Nucleotídeos/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: MRE11, a protein known to play a vital role in DNA double-strand break repair, is associated with the prognosis of a variety of tumours, but there are few studies regarding the role of MRE11 in gastric carcinoma (GC). The present study aimed to explore the clinicopathological significance and prognostic value of MRE11 expression in GC. METHODS: Data from the TCGA, GEO and Oncomine databases were analysed to assess MRE11 mRNA levels in GC. The prognostic role of the level of MRE11 mRNA was examined via the Kaplan-Meier plotter. MRE11 protein expression in tumour tissues from 155 GC patients was analysed by immunohistochemistry. Relationships between MRE11 expression and clinicopathological characteristics, overall survival (OS) and recurrence-free survival (RFS) were evaluated by Cox proportional hazards regression models and Kaplan-Meier survival curves. RESULTS: The results of bioinformatics analysis showed that MRE11 mRNA levels in GC tissues were higher than those in normal tissues (P < 0.01). Tissue microarray analysis showed that MRE11 protein expression was increased in GC tissues (P < 0.001), and MRE11 overexpression in GC tissues was significantly related to lymph node metastasis (P < 0.05), distant metastasis (P < 0.05) and tumour-node-metastasis stage (P < 0.05). Kaplan-Meier analyses showed that patients with GC who exhibited MRE11 overexpression had worse OS and RFS. According to Cox proportional hazards analyses, MRE11 overexpression was an independent prognostic factor for OS and RFS in these GC patients. CONCLUSIONS: MRE11 overexpression is significantly associated with poor prognosis, and MRE11 may serve as a prognostic biomarker in GC patients.