Yao-Jong Yang, Chung-Tai Wu, Hsiu-Chi Cheng, Wei-Ying Chen, Joseph T Tseng, Wei-Lun Chang, Bor-Shyang Sheu
{"title":"益生菌通过调节miR-185改善幽门螺杆菌相关胃β-连环蛋白和COX-2致癌信号。","authors":"Yao-Jong Yang, Chung-Tai Wu, Hsiu-Chi Cheng, Wei-Ying Chen, Joseph T Tseng, Wei-Lun Chang, Bor-Shyang Sheu","doi":"10.1186/s12929-025-01149-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>This study aimed to investigate whether probiotics can ameliorate the H. pylori-induced Wnt/β-catenin-related COX-2 carcinogenesis signaling pathway by regulating the expression of microRNAs (miRNAs).</p><p><strong>Methods: </strong>An H. pylori isolate and GES-1 cells were used to establish a COX-2-associated carcinogenesis axis. Western blot analysis was conducted to investigate Wnt/β-catenin and COX-2 signaling. Next-generation sequencing and DIANA Tools identified significant differences in miRNA expressions. The probiotics Lactobacillus acidophilus and Bifidobacterium lactis were used to study anti-carcinogenesis effects in GES-1 and miRNA-transfected GES-1 cells. The H. pylori-infected patients with intestinal metaplasia (IM) were randomly allocated into probiotic treatment or not after successful eradication, the IM regression was assessed by the 2nd esophagogastroduodenoscopy one year after treatment.</p><p><strong>Results: </strong>Pretreatment with probiotics significantly reduced H. pylori-induced nuclear β-catenin phosphorylation and COX-2 levels in GES-1 cells. Among 9 significantly altered miRNAs, miR-185 was the only miRNA targeting the Wnt/β-catenin signaling pathway. H. pylori increased miR-185 expression and upregulated COX-2 carcinogenesis through the Wnt/β-catenin pathway, but not the JAK2/STAT3 pathway. B. lactis ameliorated H. pylori-induced miR-185 expression and nuclear β-catenin/COX-2 signaling in a dose-dependent manner. In the 6-month probiotic-treated patients had a significantly higher IM regression rate than controls (intention-to-treat: 37.5 vs 11.5%, OR: 4.60, 95% CI: 1.134-18.65, p = 0.025; per-protocol: 46.2 vs 17.6%, OR: 4.00, 95% CI: 0.923-17.33, p = 0.055). Patients without IM regression had significantly higher miR-185 levels in follow-up biopsies (p < 0.01).</p><p><strong>Conclusions: </strong>Pretreatment with B. lactis ameliorated the H. pylori-induced COX-2 carcinogenesis pathway by reducing miR-185 expression, which targets Wnt/β-catenin signaling. 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Western blot analysis was conducted to investigate Wnt/β-catenin and COX-2 signaling. Next-generation sequencing and DIANA Tools identified significant differences in miRNA expressions. The probiotics Lactobacillus acidophilus and Bifidobacterium lactis were used to study anti-carcinogenesis effects in GES-1 and miRNA-transfected GES-1 cells. The H. pylori-infected patients with intestinal metaplasia (IM) were randomly allocated into probiotic treatment or not after successful eradication, the IM regression was assessed by the 2nd esophagogastroduodenoscopy one year after treatment.</p><p><strong>Results: </strong>Pretreatment with probiotics significantly reduced H. pylori-induced nuclear β-catenin phosphorylation and COX-2 levels in GES-1 cells. Among 9 significantly altered miRNAs, miR-185 was the only miRNA targeting the Wnt/β-catenin signaling pathway. H. pylori increased miR-185 expression and upregulated COX-2 carcinogenesis through the Wnt/β-catenin pathway, but not the JAK2/STAT3 pathway. B. lactis ameliorated H. pylori-induced miR-185 expression and nuclear β-catenin/COX-2 signaling in a dose-dependent manner. In the 6-month probiotic-treated patients had a significantly higher IM regression rate than controls (intention-to-treat: 37.5 vs 11.5%, OR: 4.60, 95% CI: 1.134-18.65, p = 0.025; per-protocol: 46.2 vs 17.6%, OR: 4.00, 95% CI: 0.923-17.33, p = 0.055). Patients without IM regression had significantly higher miR-185 levels in follow-up biopsies (p < 0.01).</p><p><strong>Conclusions: </strong>Pretreatment with B. lactis ameliorated the H. pylori-induced COX-2 carcinogenesis pathway by reducing miR-185 expression, which targets Wnt/β-catenin signaling. 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引用次数: 0
摘要
背景：本研究旨在探讨益生菌是否可以通过调节microRNAs （miRNAs）的表达，改善幽门螺杆菌诱导的Wnt/β-catenin相关COX-2致癌信号通路。方法：利用幽门螺杆菌分离株和GES-1细胞建立cox -2相关癌变轴。Western blot分析Wnt/β-catenin和COX-2信号通路。新一代测序和DIANA Tools鉴定出miRNA表达的显著差异。利用益生菌嗜酸乳杆菌和乳酸双歧杆菌对转染GES-1和mirna的GES-1细胞的抗癌作用进行研究。将幽门螺杆菌感染的肠化生（IM）患者在成功根除后随机分为益生菌治疗组和非益生菌治疗组，治疗1年后通过第二次食管胃十二指肠镜检查评估IM的消退情况。结果：益生菌预处理显著降低幽门螺杆菌诱导的GES-1细胞核β-catenin磷酸化和COX-2水平。在9个显著改变的miRNA中，miR-185是唯一靶向Wnt/β-catenin信号通路的miRNA。幽门螺杆菌通过Wnt/β-catenin通路上调miR-185表达，上调COX-2的致癌作用，但不通过JAK2/STAT3通路。乳杆菌以剂量依赖的方式改善幽门螺杆菌诱导的miR-185表达和核β-catenin/COX-2信号传导。在6个月的益生菌治疗中，患者的IM消退率显著高于对照组(意向治疗：37.5 vs 11.5%, OR: 4.60, 95% CI: 1.134-18.65, p = 0.025；每个方案：46.2 vs 17.6%, OR: 4.00, 95% CI: 0.923-17.33, p = 0.055)。无IM消退的患者在随访活检中miR-185水平明显升高(p)。结论：乳杆菌预处理通过降低miR-185的表达，改善了幽门螺杆菌诱导的COX-2致癌途径，miR-185靶向Wnt/β-catenin信号通路。(ClinicalTrials.gov NCT05544396)。
Probiotics ameliorate H. pylori-associated gastric β-catenin and COX-2 carcinogenesis signaling by regulating miR-185.
Background: This study aimed to investigate whether probiotics can ameliorate the H. pylori-induced Wnt/β-catenin-related COX-2 carcinogenesis signaling pathway by regulating the expression of microRNAs (miRNAs).
Methods: An H. pylori isolate and GES-1 cells were used to establish a COX-2-associated carcinogenesis axis. Western blot analysis was conducted to investigate Wnt/β-catenin and COX-2 signaling. Next-generation sequencing and DIANA Tools identified significant differences in miRNA expressions. The probiotics Lactobacillus acidophilus and Bifidobacterium lactis were used to study anti-carcinogenesis effects in GES-1 and miRNA-transfected GES-1 cells. The H. pylori-infected patients with intestinal metaplasia (IM) were randomly allocated into probiotic treatment or not after successful eradication, the IM regression was assessed by the 2nd esophagogastroduodenoscopy one year after treatment.
Results: Pretreatment with probiotics significantly reduced H. pylori-induced nuclear β-catenin phosphorylation and COX-2 levels in GES-1 cells. Among 9 significantly altered miRNAs, miR-185 was the only miRNA targeting the Wnt/β-catenin signaling pathway. H. pylori increased miR-185 expression and upregulated COX-2 carcinogenesis through the Wnt/β-catenin pathway, but not the JAK2/STAT3 pathway. B. lactis ameliorated H. pylori-induced miR-185 expression and nuclear β-catenin/COX-2 signaling in a dose-dependent manner. In the 6-month probiotic-treated patients had a significantly higher IM regression rate than controls (intention-to-treat: 37.5 vs 11.5%, OR: 4.60, 95% CI: 1.134-18.65, p = 0.025; per-protocol: 46.2 vs 17.6%, OR: 4.00, 95% CI: 0.923-17.33, p = 0.055). Patients without IM regression had significantly higher miR-185 levels in follow-up biopsies (p < 0.01).
Conclusions: Pretreatment with B. lactis ameliorated the H. pylori-induced COX-2 carcinogenesis pathway by reducing miR-185 expression, which targets Wnt/β-catenin signaling. (ClinicalTrials.gov, NCT05544396).
期刊介绍：
The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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