RRC ID 67022
著者 Zhu S, Khalafi S, Chen Z, Poveda J, Peng D, Lu H, Soutto M, Que J, Garcia-Buitrago M, Zaika A, El-Rifai W.
タイトル Silencing of miR490-3p by H. pylori activates DARPP-32 and induces resistance to gefitinib.
ジャーナル Cancer Lett
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.
巻・号 491
ページ 87-96
公開日 2020-10-28
DOI 10.1016/j.canlet.2020.07.014
PII S0304-3835(20)30369-4
PMID 32735911
PMC PMC7541786
MeSH Animals Cell Line, Tumor DNA Methylation Dopamine and cAMP-Regulated Phosphoprotein 32 / physiology* Drug Resistance, Neoplasm Gefitinib / therapeutic use* Helicobacter Infections / complications Helicobacter pylori / pathogenicity* Humans Mice Mice, Inbred C57BL MicroRNAs / antagonists & inhibitors MicroRNAs / physiology* Receptor, Muscarinic M2 / genetics Stomach Neoplasms / drug therapy* Stomach Neoplasms / genetics Stomach Neoplasms / microbiology
IF 7.36
リソース情報
ヒト・動物細胞 MKN45(RCB1001)