Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation

Bin Liu; Ihtisham Bukhari; Fazhan Li; Feifei Ren; Ihtisham Bukhari; Xue Xia; Baitong Hu; Haipeng Liu; Thomas F Meyer; Barry J Marshall; Alfred Tay; Yuming Fu; Wanqing Wu; Youcai Tang; Yang Mi; Pengyuan Zheng

doi:10.1016/j.jare.2024.04.002

Enhanced LRP8 expression induced by Helicobacter pylori drives gastric cancer progression by facilitating β-Catenin nuclear translocation

J Adv Res. 2024 Apr 10:S2090-1232(24)00131-0. doi: 10.1016/j.jare.2024.04.002. Online ahead of print.

Authors

Bin Liu¹, Ihtisham Bukhari², Fazhan Li¹, Feifei Ren², Ihtisham Bukhari², Xue Xia², Baitong Hu¹, Haipeng Liu³, Thomas F Meyer⁴, Barry J Marshall⁵, Alfred Tay⁵, Yuming Fu⁶, Wanqing Wu⁶, Youcai Tang⁷, Yang Mi⁸, Pengyuan Zheng⁹

Affiliations

¹ Key Laboratory of Helicobacter pylori&Microbiota and Gastrointestinal Cancer of Henan Province, 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.
² Key Laboratory of Helicobacter pylori&Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
³ Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
⁴ Max Planck Institute for Infection Biology, Department of Molecular Biology, 10117 Berlin, Germany; Laboratory of Infection Oncology, Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts University of Kiel, Kiel, Germany.
⁵ Helicobacter Pylori Research Laboratory, School of Biomedical Sciences, Marshall Centre for Infectious Disease Research and Training, University of Western Australia, Nedlands 6009, Australia.
⁶ Gastrointestinal Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
⁷ Department of Pediatrics, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
⁸ Key Laboratory of Helicobacter pylori&Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: yangmi198@zzu.edu.cn.
⁹ Key Laboratory of Helicobacter pylori&Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: pyzheng@zzu.edu.cn.

PMID: 38609049
DOI: 10.1016/j.jare.2024.04.002

Abstract

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 roles 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.

Keywords: Gastric cancer; Helicobacter pylori; LRP8; Organoids; Wnt/β-catenin.