The novel ZEB1-upregulated protein PRTG induced by Helicobacter pylori infection promotes gastric carcinogenesis through the cGMP/PKG signaling pathway

Cell Death Dis. 2021 Feb 4;12(2):150. doi: 10.1038/s41419-021-03440-1.

Abstract

Helicobacter pylori (H. pylori) is listed as a class I carcinogen in human gastric cancer; however, the underlying mechanisms are poorly understood. In this study, we identified Protogenin (PRTG) was upregulated in both gastric cancer tissues and H. pylori-infected tissues by analyzing dysregulated genes in TCGA and GEO databases. Importantly, upregulated PRTG predicted poor prognosis of gastric cancer patients and integrative analysis revealed that PRTG served as an oncogenic protein in gastric cancer and was required for H. pylori-mediated tumorigenic activities in in vitro cellular and in vivo tumor-bearing mouse models. Mechanistically, H. pylori infection enhanced PRTG expression by promoting transcriptional factor ZEB1 stabilization and recruitment to the PRTG promoter, and which then activated the sub-following cGMP/PKG signaling pathway in bioinformatic and cellular studies. Cellular studies further confirmed that PRTG depended on activating cGMP/PKG axis to promote proliferation, metastasis, and chemoresistance of gastric cancer cells. The PKG inhibitor KT5823 played synergistic anti-tumor effects with cisplatin and paclitaxel to gastric cancer cells in in vitro cellular and in vivo tumor-bearing mouse models. Taken together, our findings suggested that H. pylori infection depends on ZEB1 to induce PRTG upregulation, and which leading to the development and progression of gastric cancer through activating cGMP/PKG signaling pathway. Blocking PRTG/cGMP/PKG axis, therefore, presents a promising novel therapeutic strategy for gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Cisplatin / pharmacology
  • Cyclic GMP / metabolism*
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP-Dependent Protein Kinases / metabolism*
  • Databases, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • Helicobacter Infections / microbiology*
  • Helicobacter pylori / pathogenicity*
  • Host-Pathogen Interactions
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Nude
  • Middle Aged
  • Neoplasm Invasiveness
  • Paclitaxel / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Second Messenger Systems
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / microbiology*
  • Stomach Neoplasms / pathology
  • Up-Regulation
  • Xenograft Model Antitumor Assays
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*

Substances

  • Membrane Proteins
  • Protein Kinase Inhibitors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • protogenin, human
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic GMP
  • Paclitaxel
  • Cisplatin