Silencing of miR490-3p by H. pylori activates DARPP-32 and induces resistance to gefitinib.
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
Receptor, Muscarinic M2
/ genetics
Stomach Neoplasms
/ drug therapy
AKT
DARPP-32
Gastric cancer
Gefitinib
Methylation
STAT3
miRNA
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
28 10 2020
28 10 2020
Historique:
received:
15
04
2020
revised:
02
07
2020
accepted:
13
07
2020
pubmed:
1
8
2020
medline:
23
2
2021
entrez:
1
8
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32735911
pii: S0304-3835(20)30369-4
doi: 10.1016/j.canlet.2020.07.014
pmc: PMC7541786
mid: NIHMS1620391
pii:
doi:
Substances chimiques
CHRM2 protein, human
0
Dopamine and cAMP-Regulated Phosphoprotein 32
0
MIRN590 microRNA, human
0
MicroRNAs
0
PPP1R1B protein, human
0
Receptor, Muscarinic M2
0
Gefitinib
S65743JHBS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
87-96Subventions
Organisme : NCI NIH HHS
ID : R01 CA138833
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206564
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA093999
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA240139
Pays : United States
Organisme : BLRD VA
ID : I01 BX002115
Pays : United States
Organisme : BLRD VA
ID : IK6 BX003787
Pays : United States
Organisme : BLRD VA
ID : I01 BX001179
Pays : United States
Informations de copyright
Published by Elsevier B.V.
Références
Clin Cancer Res. 2018 Apr 15;24(8):1905-1916
pubmed: 29386219
Recent Results Cancer Res. 2011;185:173-83
pubmed: 21822827
CA Cancer J Clin. 2019 Jan;69(1):7-34
pubmed: 30620402
mBio. 2018 Apr 24;9(2):
pubmed: 29691341
Oncotarget. 2017 Jul 12;8(46):81572-81582
pubmed: 29113415
Gastroenterology. 2005 May;128(6):1567-78
pubmed: 15887152
World J Gastroenterol. 2012 Sep 28;18(36):5129-34
pubmed: 23049225
Sci Rep. 2016 Feb 05;6:20502
pubmed: 26846307
Gastroenterology. 2011 Nov;141(5):1738-48.e1-2
pubmed: 21741919
J Med Life. 2017 Apr-Jun;10(2):112-117
pubmed: 28616085
Int J Oncol. 2017 Jun;50(6):2079-2090
pubmed: 28440397
Surgery. 2010 Aug;148(2):354-63
pubmed: 20580047
Gut Liver. 2018 Jan 15;12(1):58-66
pubmed: 28950691
Clin Cancer Res. 2018 Nov 15;24(22):5724-5734
pubmed: 29844130
Cancer Res. 2002 Jul 15;62(14):4061-4
pubmed: 12124342
Gastroenterology. 2018 Nov;155(5):1372-1382.e17
pubmed: 29990487
World J Gastroenterol. 2016 Aug 14;22(30):6876-89
pubmed: 27570424
Curr Opin Gastroenterol. 2002 Jan;18(1):15-25
pubmed: 17031225
World J Gastroenterol. 2014 Apr 28;20(16):4536-45
pubmed: 24782606
Am J Clin Oncol. 2017 Dec;40(6):543-551
pubmed: 26125303
Eur Rev Med Pharmacol Sci. 2019 Jan;23(2):539-546
pubmed: 30720161
CA Cancer J Clin. 2020 Jan;70(1):7-30
pubmed: 31912902
Cancer Res. 2005 Aug 1;65(15):6583-92
pubmed: 16061638
Anticancer Agents Med Chem. 2016;16(3):318-34
pubmed: 26234359
Mol Cancer. 2012 Jan 30;11:5
pubmed: 22289355
Pathogens. 2019 Feb 13;8(1):
pubmed: 30781778
PLoS One. 2013;8(1):e54344
pubmed: 23372710
Cancer Cell Int. 2018 Apr 2;18:50
pubmed: 29618949
Mol Cancer. 2010 Sep 13;9:240
pubmed: 20836878
Oncogene. 2019 Jul;38(29):5805-5816
pubmed: 31235784
Cochrane Database Syst Rev. 2017 Jun 27;6:CD007047
pubmed: 28654140
World J Clin Oncol. 2015 Oct 10;6(5):111-32
pubmed: 26468448
Int J Mol Sci. 2018 Feb 03;19(2):
pubmed: 29401683
JAMA Oncol. 2019 Dec 1;5(12):1749-1768
pubmed: 31560378
Nucleic Acids Res. 2001 May 1;29(9):e45
pubmed: 11328886
J Transl Med. 2016 May 20;14(1):143
pubmed: 27197967
Clin Cancer Res. 2012 Jul 15;18(14):3889-900
pubmed: 22589394
Gastroenterology. 2019 Mar;156(4):1127-1139.e8
pubmed: 30502323
Gut. 2017 May;66(5):761-762
pubmed: 27590997
Cancer Lett. 2016 Jun 28;376(1):178-87
pubmed: 27037061
Cancer Res. 2008 Jan 15;68(2):379-87
pubmed: 18199531
Breast Cancer Res Treat. 2010 Feb;120(1):47-57
pubmed: 19301121
Int J Cancer. 2018 Aug 1;143(3):597-609
pubmed: 29574700