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) |