Silencing of miR490–3p by H. pylori activates DARPP-32 and induces resistance to gefitinib

Shoumin Zhu, Shayan Khalafi, Zheng Chen, Julio Poveda, Dunfa Peng, Heng Lu, Mohammed Soutto, Jianwen Que, Monica Garcia-Buitrago, Alexander Zaika, Wael El-Rifai

Research output: Contribution to journalArticle

Abstract

Infection with Helicobacter pylori (H. pylori) is the main risk factor for gastric carcinogenesis. In this study, we investigated the expression, molecular functions, and downstream effectors of miR490–3p in gastric cancer. We used in vitro and in vivo models to investigate the role of H. pylori in regulating miR490–3p, DARPP-32-dependent functions, and therapeutic resistance. Human and mouse neoplastic gastric lesions demonstrated a negative correlation between DARPP-32 and miR490–3p expression (R = −0.58, P < 0.01). This was also detected following infection with H. pylori (R = −0.66, P < 0.01). Molecular assays confirmed DARPP-32 as a direct target of miR490–3p. CHRM2, the host gene of miR490–3p, was hypermethylated and downregulated in neoplastic gastric tissues (P < 0.05). H. pylori induced methylation and downregulation of CHRM2 and miR490–3p. Functionally, the reconstitution of miR490–3p sensitized cancer cells to gefitinib by inactivating DRAPP-32-dependent AKT and STAT3 pathways. Patients with low miR490–3p or high DARPP-32 expression had decreased overall survival (P < 0.05). Hypermethylation-mediated silencing of CHRM2 and miR490–3p by H. pylori increased DARPP-32 expression. Downregulation of miR490–3p in gastric cancer plays a role in gefitinib response by inducing DARPP-32-mediated activation of PI3K/AKT, STAT3 signaling pathways.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalCancer letters
Volume491
DOIs
StatePublished - Oct 28 2020

Keywords

  • AKT
  • DARPP-32
  • Gastric cancer
  • Gefitinib
  • Methylation
  • miRNA
  • STAT3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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