Helicobacter pylori-Induced Progranulin Promotes the Progression of the Gastric Epithelial Cell Cycle by Regulating CDK4

J Microbiol Biotechnol. 2022 Jul 28;32(7):844-854. doi: 10.4014/jmb.2203.03053. Epub 2022 Jun 20.

Abstract

Helicobacter pylori, a group 1 carcinogen, colonizes the stomach and affects the development of stomach diseases. Progranulin (PGRN) is an autocrine growth factor that regulates multiple cellular processes and plays a tumorigenic role in many tissues. Nevertheless, the mechanism of action of PGRN in gastric cancer caused by H. pylori infection remains unclear. Here, we investigated the role of PGRN in cell cycle progression and the cell proliferation induced by H. pylori infection. We found that the increased PGRN was positively associated with CDK4 expression in gastric cancer tissue. PGRN was upregulated by H. pylori infection, thereby promoting cell proliferation, and that enhanced level of proliferation was reduced by PGRN inhibitor. CDK4, a target gene of PGRN, is a cyclin-dependent kinase that binds to cyclin D to promote cell cycle progression, which was upregulated by H. pylori infection. We also showed that knockdown of CDK4 reduced the higher cell cycle progression caused by upregulated PGRN. Moreover, when the PI3K/Akt signaling pathway (which is promoted by PGRN) was blocked, the upregulation of CDK4 mediated by PGRN was reduced. These results reveal the potential mechanism by which PGRN plays a major role through CDK4 in the pathological mechanism of H. pylori infection.

Keywords: CDK4; Helicobacter pylori; PGRN; cell cycle; gastric epithelial cells.

MeSH terms

  • Cell Cycle
  • Cell Proliferation
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Epithelial Cells / metabolism
  • Gastric Mucosa / pathology
  • Helicobacter Infections* / pathology
  • Helicobacter pylori* / physiology
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Progranulins / metabolism
  • Stomach Neoplasms* / pathology

Substances

  • Progranulins
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4