| RRC ID |
58596
|
| 著者 |
Gomaa A, Peng D, Chen Z, Soutto M, Abouelezz K, Corvalan A, El-Rifai W.
|
| タイトル |
Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers.
|
| ジャーナル |
Sci Rep
|
| Abstract |
Aurora kinase A (AURKA) is frequently overexpressed in several cancers. miRNA sequencing and bioinformatics analysis indicated significant downregulation of miR-4715-3p. We found that miR-4715-3p has putative binding sites on the 3UTR region of AURKA. Upper gastrointestinal adenocarcinoma (UGC) tissue samples and cell models demonstrated significant overexpression of AURKA with downregulation of miR-4715-3p. Luciferase reporter assays confirmed binding of miR-4715-3p on the 3UTR region of AURKA. miR-4715-3p mediated a reduction in AURKA levels leading to G2/M delay, chromosomal polyploidy, and cell death. We also detected a remarkable decrease in GPX4, an inhibitor of ferroptosis, with an increase in cleaved PARP and caspase-3. Inhibition of AURKA using siRNA produced similar results, suggesting a possible link between AURKA and GPX4. Analysis of UGC samples and cell models demonstrated increased methylation levels of several CpG nucleotides upstream of miR-4715-3p. 5-Aza-2'-deoxycytidine induced demethylation of several CpG nucleotides, restoring miR-4715-3p expression, leading to downregulation of AURKA. In conclusion, our data identified a novel epigenetic mechanism mediating silencing of miR-4715-3p and induction of AURKA in UGCs. Inhibition of AURKA or reconstitution of miR-4715-3p inhibited GPX4 and induced cell death, suggesting a link between AURKA and ferroptosis.
|
| 巻・号 |
9(1)
|
| ページ |
16970
|
| 公開日 |
2019-11-18
|
| DOI |
10.1038/s41598-019-53174-6
|
| PII |
10.1038/s41598-019-53174-6
|
| PMID |
31740746
|
| PMC |
PMC6861278
|
| MeSH |
3' Untranslated Regions
Antineoplastic Agents / pharmacology
Aurora Kinase A / genetics*
Cisplatin / pharmacology
DNA Methylation
Epigenesis, Genetic*
Gastrointestinal Neoplasms / genetics*
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
MicroRNAs / genetics*
Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
Polyploidy
Stomach Neoplasms / drug therapy
Stomach Neoplasms / genetics
Stomach Neoplasms / mortality
Stomach Neoplasms / pathology
Upper Gastrointestinal Tract
|
| IF |
3.998
|
| 引用数 |
1
|
| リソース情報 |
| ヒト・動物細胞 |
MKN45(RCB1001) |
