幽门螺杆菌诱导的LRP8表达增强通过促进β-连环蛋白核转位驱动胃癌进展。
Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation.
作者信息
Liu Bin, Bukhari Ihtisham, Li Fazhan, Ren Feifei, Xia Xue, Hu Baitong, Liu Haipeng, Meyer Thomas F, Marshall Barry J, Tay Alfred, Fu Yuming, Wu Wanqing, Tang Youcai, Mi Yang, Zheng Peng-Yuan
机构信息
Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China; Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, Henan, China.
Henan Key Laboratory for Helicobacter pylori and Digestive Tract Microecology, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
出版信息
J Adv Res. 2025 Mar;69:299-312. doi: 10.1016/j.jare.2024.04.002. Epub 2024 Apr 10.
INTRODUCTION
Helicobacter pylori (H. pylori) infection has been associated with gastric carcinogenesis. However, the precise involvement of LRP8, the low-density lipoprotein receptor-related protein 8, in H. pylori pathogenesis and gastric cancer (GC) remains poorly understood.
OBJECTIVES
To investigate the potential role of LRP8 in H. pylori infection and gastric carcinogenesis.
METHODS
Three-dimensional human-derived gastric organoids (hGO) and gastric cancer organoids (hGCO) were synthesized from the tissues obtained from human donors. In this work, multi-omics combined with in vivo and in vitro studies were conducted to investigate the potential involvement of LRP8 in H. pylori-induced GC.
RESULTS
We found that H. pylori infection significantly upregulated the expression of LRP8 in human GC tissues, cells, organoids, and mouse gastric mucous. In particular, LRP8 exhibited a distinct enrichment in cancer stem cells (CSC). Functionally, silencing of LRP8 affected the formation and proliferation of tumor spheroids, while increased expression of LRP8 was associated with increased proliferation and stemness of GC cells and organoids. Mechanistically, LRP8 promotes the binding of E-cadherin to β-catenin, thereby promoting nuclear translocation and transcriptional activity of β-catenin. Furthermore, LRP8 interacts with the cytotoxin-associated gene A (CagA) to form the CagA/LRP8/β-catenin complex. This complex further amplifies H. pylori-induced β-catenin nuclear translocation, leading to increased transcription of inflammatory factors and CSC markers. Clinical analysis demonstrated that abnormal overexpression of LRP8 is correlated with a poor prognosis and resistance to 5-Fluorouracil in patients with GC.
CONCLUSION
Our findings provide valuable information on the molecular intricacies of H. pylori-induced gastric carcinogenesis, offering potential therapeutic targets and prognostic markers for GC.
引言
幽门螺杆菌（H. pylori）感染与胃癌发生有关。然而，低密度脂蛋白受体相关蛋白8（LRP8）在幽门螺杆菌发病机制和胃癌（GC）中的具体作用仍知之甚少。
目的
研究LRP8在幽门螺杆菌感染和胃癌发生中的潜在作用。
方法
从人类供体组织中合成三维人源胃类器官（hGO）和胃癌类器官（hGCO）。在本研究中，进行了多组学结合体内和体外研究，以探讨LRP8在幽门螺杆菌诱导的胃癌中的潜在作用。
结果
我们发现幽门螺杆菌感染显著上调了人胃癌组织、细胞、类器官和小鼠胃黏液中LRP8的表达。特别是，LRP8在癌症干细胞（CSC）中表现出明显的富集。在功能上，LRP8的沉默影响肿瘤球的形成和增殖，而LRP8表达的增加与GC细胞和类器官的增殖增加及干性增强有关。机制上，LRP8促进E-钙黏蛋白与β-连环蛋白的结合，从而促进β-连环蛋白的核转位和转录活性。此外，LRP8与细胞毒素相关基因A（CagA）相互作用形成CagA/LRP8/β-连环蛋白复合物。该复合物进一步放大幽门螺杆菌诱导的β-连环蛋白核转位，导致炎症因子和CSC标志物的转录增加。临床分析表明，LRP8的异常过表达与GC患者的预后不良和对5-氟尿嘧啶的耐药性相关。
结论
我们的研究结果为幽门螺杆菌诱导的胃癌发生的分子复杂性提供了有价值的信息，为GC提供了潜在的治疗靶点和预后标志物。
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