PDF(Pubmed)
Abstract：
Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2\'s role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.
摘要：
幽门螺杆菌（HP）感染引发并促进胃癌的发生。ONECUT2显示出肿瘤诊断的希望，预后,和治疗。这项研究探讨了ONECUT2的作用和HP感染相关胃癌发生的具体机制，为靶向ONECUT2作为胃癌（GC）的治疗策略提供了基础。多维数据支持ONECUT2、HP感染、和GC发病机制。HP感染通过NFκB上调ONECUT2转录活性。体外和体内实验表明，ONECUT2增加了GC细胞的干性。ONECUT2也显示抑制PPP2R4转录，导致PP2A活性降低，进而增加AKT/β-连环蛋白磷酸化。AKT/β-catenin磷酸化促进β-catenin易位到细胞核，启动GC细胞下游干性相关基因的转录。HP感染通过ONECUT2诱导下调ONECUT2引发的AKT和β-catenin磷酸化降低。临床生存分析表明，高ONECUT2表达可能表明GC预后不良。这项研究强调了ONECUT2通过PPP2R4/AKT/β-catenin信号通路增强细胞干性，在促进HP感染相关GC中发挥的关键作用。这些发现表明了有希望的治疗策略和GC治疗的潜在目标。
