TY - JOUR
T1 - Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation
AU - Liu, Bin
AU - Bukhari, Ihtisham
AU - Li, Fazhan
AU - Ren, Feifei
AU - Xia, Xue
AU - Hu, Baitong
AU - Liu, Haipeng
AU - Meyer, Thomas F.
AU - Marshall, Barry J.
AU - Tay, Alfred
AU - Fu, Yuming
AU - Wu, Wanqing
AU - Tang, Youcai
AU - Mi, Yang
AU - Zheng, Peng Yuan
N1 - Publisher Copyright:
© 2023
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - CagA
KW - Gastric cancer
KW - Helicobacter pylori
KW - LRP8
KW - Organoids
KW - Wnt/β-catenin
UR - http://www.scopus.com/inward/record.url?scp=85192098558&partnerID=8YFLogxK
U2 - 10.1016/j.jare.2024.04.002
DO - 10.1016/j.jare.2024.04.002
M3 - Article
C2 - 38609049
AN - SCOPUS:85192098558
SN - 2090-1232
JO - Journal of Advanced Research
JF - Journal of Advanced Research
ER -
