Yang Yao-Jong, Wu Chung-Tai, Cheng Hsiu-Chi, Chen Wei-Ying, Tseng Joseph T, Chang Wei-Lun, Sheu Bor-Shyang
Department of Pediatrics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, #138 Sheng Li Road, Tainan, 70428, Taiwan.
Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
J Biomed Sci. 2025 Jun 3;32(1):55. doi: 10.1186/s12929-025-01149-3.
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).
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.
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).
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).
本研究旨在探讨益生菌是否可通过调节微小RNA（miRNA）的表达来改善幽门螺杆菌诱导的与Wnt/β-连环蛋白相关的COX-2致癌信号通路。
使用一株幽门螺杆菌分离株和GES-1细胞建立与COX-2相关的致癌轴。进行蛋白质免疫印迹分析以研究Wnt/β-连环蛋白和COX-2信号传导。通过下一代测序和DIANA工具鉴定miRNA表达的显著差异。使用嗜酸乳杆菌和双歧杆菌研究其在GES-1细胞和转染了miRNA的GES-1细胞中的抗癌作用。幽门螺杆菌感染的肠化生（IM）患者在成功根除幽门螺杆菌后被随机分为接受益生菌治疗组和未接受益生菌治疗组，治疗一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。
益生菌预处理显著降低了幽门螺杆菌诱导的GES-1细胞中核β-连环蛋白磷酸化和COX-2水平。在9种显著改变的miRNA中，miR-185是唯一靶向Wnt/β-连环蛋白信号通路的miRNA。幽门螺杆菌通过Wnt/β-连环蛋白途径而非JAK2/STAT3途径增加miR-185表达并上调COX-2致癌作用。双歧杆菌以剂量依赖的方式改善了幽门螺杆菌诱导的miR-185表达以及核β-连环蛋白/COX-2信号传导。在接受益生菌治疗6个月的患者中，IM消退率显著高于对照组（意向性分析：37.5%对11.5%，OR：4.60，95%CI：1.134 - 18.65，p = 0.025；符合方案分析：46.2%对17.6%，OR：4.00，95%CI：0.923 - 17.33，p = 0.055）。未出现IM消退的患者在随访活检中的miR-185水平显著更高（p < 0.01）。
双歧杆菌预处理通过降低靶向Wnt/β-连环蛋白信号传导的miR-185表达，改善了幽门螺杆菌诱导的COX-2致癌途径。（ClinicalTrials.gov，NCT05544396）
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