In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms.
Alkaloids
/ pharmacology
Animals
Antineoplastic Agents, Phytogenic
/ pharmacology
Carcinoma, Hepatocellular
/ drug therapy
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Epithelial-Mesenchymal Transition
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ genetics
Liver Neoplasms
/ drug therapy
Mice, Nude
MicroRNAs
/ genetics
Neoplasm Recurrence, Local
Quinolizines
/ pharmacology
Sophora
/ chemistry
Xenograft Model Antitumor Assays
Matrines
EMT
HIF-1α
Hepatocellular carcinoma
Matrine
Metastasis
MiR-199a-5p
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
20
02
2020
revised:
21
09
2020
accepted:
18
04
2021
pubmed:
25
5
2021
medline:
7
7
2021
entrez:
24
5
2021
Statut:
ppublish
Résumé
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine. MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine. Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine. Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy.
Sections du résumé
BACKGROUNDS
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C
PURPOSE
OBJECTIVE
We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine.
METHODS
METHODS
MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine.
RESULTS
RESULTS
Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine.
CONCLUSIONS
CONCLUSIONS
Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy.
Identifiants
pubmed: 34029939
pii: S0944-7113(21)00122-7
doi: 10.1016/j.phymed.2021.153580
pii:
doi:
Substances chimiques
Alkaloids
0
Antineoplastic Agents, Phytogenic
0
HIF1A protein, human
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
MicroRNAs
0
Quinolizines
0
mirn199 microRNA, human
0
Matrines
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
153580Informations de copyright
Copyright © 2021 Elsevier GmbH. All rights reserved.