5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway.
5-azacytidine
E2F1
MMP-2
ROCK2
cell cycle
hepatocellular carcinoma
miR-139-5p
migration
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
23 Mar 2022
23 Mar 2022
Historique:
received:
30
12
2021
revised:
14
02
2022
accepted:
18
03
2022
entrez:
12
4
2022
pubmed:
13
4
2022
medline:
13
4
2022
Statut:
epublish
Résumé
For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects. 5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC. 5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27 We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27
Sections du résumé
BACKGROUND
BACKGROUND
For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects.
METHODS
METHODS
5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC.
RESULTS
RESULTS
5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27
CONCLUSION
CONCLUSIONS
We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27
Identifiants
pubmed: 35406401
pii: cancers14071630
doi: 10.3390/cancers14071630
pmc: PMC8996928
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Fondazione Benefica Kathleen Foreman Casali of Trieste, Italy
ID : no number
Organisme : Beneficentia Stiftung" of Vaduz Liechtenstein
ID : no number
Organisme : Slovenian Research Agency (ARRS)
ID : P3-0003
Organisme : Progetto HEaD "HIGHER EDUCATION AND DEVELOPMENT" UNITS, Fondo sociale Europeo 2014/2020, Asse 3, Programma specifico 25/15
ID : FP168562300
Organisme : Italian Ministry of Foreign Affairs and International Cooperation
ID : VN21GR01
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