Dihydromyricetin reverses Herceptin resistance by up-regulating miR-98-5p and inhibiting IGF1R/HER2 dimer formation in SKBR3 cells.
10.12122/j.issn.1673-4254.2022.02.06
- Author:
Ming Liang ZHANG
1
;
Chen Xu GUO
1
;
Yun Mian CHU
1
;
Rui XU
1
;
Fa Xiang YIN
1
;
Jun QIAN
1
Author Information
1. Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China.
- Publication Type:Journal Article
- Keywords:
Herceptin;
breast cancer;
dihydromyricetin;
drug resistance;
heterodimer;
miR-98-5p
- MeSH:
Animals;
Cell Line, Tumor;
Flavonols/pharmacology*;
Humans;
Mice;
MicroRNAs/metabolism*;
Receptor, IGF Type 1;
Trastuzumab
- From:
Journal of Southern Medical University
2022;42(2):207-214
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the effect of dihydromyricetin on the expression of miR-98-5p and its mechanism in the development of Herceptin resistance in SKBR3 cells.
METHODS:The expression of IGF2 and miR-98-5p and their interaction relationship were analyzed by bioinformatics analysis through TargetScan online databases. SKBR3 cells and drug-resistant SKBR3-R cells were cultured in cell experiments. Xenograft tumor mice were constructed by SKBR3 and SKBR3-R cells. Proteins were detected by western blotting and immunohistochemistry. Transfected cells were constructed by shRNA lentivirus vectors. RT-QPCR was used to detect RNA. Cell proliferation was detected by MTS method. Cell jnvasion was detected by Transwell assay. Luciferase reporting assays were used to verify RNA interactions. IGF-1R/HER2 heterodimer was determined by immunocoprecipitation.
RESULTS:The expression of IGF2, p-IGF1R, p-Akt and p-S6K in SKBR3-R cells were significantly higher than those in SKBR3 cells, while the expression of PTEN protein was lower in SKBR3-R cells (P < 0.05). IGF1R/HER2 heterodimer in SKBR3-R cells was significantly increased (P < 0.01).The expression of IGF2 and invasion ability were significantly reduced while transfected with miR-98-5p in SKBR3-R cells (P < 0.05), but the IGF2 mRNA were no difference in both cells (P > 0.05). The expression of miR-98-5p was up-regulated and IGF2 was decreased in drug-resistant xenograft tumor mice after feeding with dihydromyricetin, and the tumor became more sensitivity to Herceptin (P < 0.05).
CONCLUSION:Dihydromyricetin could induce the expression of miR-98-5p, which binds to IGF2 mRNA to reduce IGF2 expression, inhibit the IGF-1R/HER2 formation, thereby reversing cell resistance to Herceptin in SKBR3-R cells.
