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dc.contributor.authorTonon, Federica
dc.contributor.authorCemazar, Maja
dc.contributor.authorKamensek, Urska
dc.contributor.authorZennaro, Cristina
dc.contributor.authorPozzato, Gabriele
dc.contributor.authorCaserta, Sergio
dc.contributor.authorAscione, Flora
dc.contributor.authorGrassi, Mario
dc.contributor.authorGuido, Stefano
dc.contributor.authorFerrari, Cinzia
dc.contributor.authorCansolino, Laura
dc.contributor.authorTrotta, Francesco
dc.contributor.authorKuzmanov, Biljana Grcar
dc.contributor.authorForte, Giancarlo
dc.contributor.authorMartino, Fabiana
dc.contributor.authorPerrone, Francesca
dc.contributor.authorBomben, Riccardo
dc.contributor.authorGattei, Valter
dc.contributor.authorElvassore, Nicola
dc.contributor.authorMurano, Erminio
dc.contributor.authorTruong, Nhung Hai
dc.contributor.authorOlson, Michael
dc.contributor.authorFarra, Rossella
dc.contributor.authorGrassi, Gabriele
dc.contributor.authorDapas, Barbara
dc.description.abstractBACKGROUND: 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: 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: 5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27kip1, resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27kip1 led to G2/M accumulation. Finally, we observed a decrease in MMP-2 levels, a stimulator of HCC cell migration. Aza effects were confirmed in the mouse model; in the zebrafish model, we also demonstrated the downregulation of tumor neo-angiogenesis, and in the orthotopic rat model, we observed impaired N1-S1 grafting in a healthy liver. CONCLUSION: 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/p27kip1/MMP-2 in HCC.
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.sourcenlmid: 101526829
dc.sourceessn: 2072-6694
dc.title5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway.
prism.publicationNameCancers (Basel)
dc.contributor.orcidCemazar, Maja [0000-0002-1418-1928]
dc.contributor.orcidKamensek, Urska [0000-0002-0481-4226]
dc.contributor.orcidZennaro, Cristina [0000-0003-4755-1064]
dc.contributor.orcidCaserta, Sergio [0000-0002-4400-0059]
dc.contributor.orcidGrassi, Mario [0000-0002-3532-3200]
dc.contributor.orcidGuido, Stefano [0000-0002-9247-6852]
dc.contributor.orcidFerrari, Cinzia [0000-0001-8356-7472]
dc.contributor.orcidCansolino, Laura [0000-0002-8330-1532]
dc.contributor.orcidForte, Giancarlo [0000-0002-1341-1023]
dc.contributor.orcidBomben, Riccardo [0000-0002-8746-9404]
dc.contributor.orcidOlson, Michael [0000-0003-3428-3507]
dc.contributor.orcidGrassi, Gabriele [0000-0001-9704-6651]

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International