Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development.
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Carcinoma, Pancreatic Ductal
/ genetics
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Inbred C57BL
MicroRNAs
/ genetics
Mutation
Pancreatic Neoplasms
/ genetics
Prognosis
Proto-Oncogene Proteins p21(ras)
/ genetics
Tumor Cells, Cultured
Journal
Cancer prevention research (Philadelphia, Pa.)
ISSN: 1940-6215
Titre abrégé: Cancer Prev Res (Phila)
Pays: United States
ID NLM: 101479409
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
02
02
2020
revised:
24
03
2020
accepted:
21
04
2020
pubmed:
16
5
2020
medline:
6
7
2021
entrez:
16
5
2020
Statut:
ppublish
Résumé
Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts.
Identifiants
pubmed: 32409593
pii: 1940-6207.CAPR-20-0053
doi: 10.1158/1940-6207.CAPR-20-0053
pmc: PMC7372516
mid: NIHMS1589073
doi:
Substances chimiques
Biomarkers, Tumor
0
MIRN21 microRNA, mouse
0
MicroRNAs
0
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
569-582Subventions
Organisme : NCI NIH HHS
ID : R01 CA184926
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007334
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009071
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008752
Pays : United States
Informations de copyright
©2020 American Association for Cancer Research.
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