5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F22%3A00077640" target="_blank" >RIV/00159816:_____/22:00077640 - isvavai.cz</a>

Result on the web

<a href="https://www.mdpi.com/2072-6694/14/7/1630" target="_blank" >https://www.mdpi.com/2072-6694/14/7/1630</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/cancers14071630" target="_blank" >10.3390/cancers14071630</a>

Result language

angličtina

Original language name

5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway

Original language description

Simple Summary For hepatocellular carcinoma (HCC), the second most common cause of cancer-related death, effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to the development of HCC, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. However, despite the potential efficacy of 5-Aza in HCC, most of its mechanisms of action are still unknown. Here, we investigate the phenotypic/molecular effects of 5-Aza with a focus on miR-139-5p. Using multiple in vitro and in vivo models of HCC, we show for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn downregulates the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. These observations elucidate the mechanisms of action of 5-Aza in HCC, strengthen its therapeutic potential, and provide novel information about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/MMP-2 in HCC. 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: 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 p27(kip1), resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27(kip1) 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/p27(kip1)/MMP-2 in HCC.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30204 - Oncology

Project

<a href="/en/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Unveiling the molecular determinants of agingto design new therapeutics</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

CANCERS

ISSN

2072-6694

e-ISSN

2072-6694

Volume of the periodical

14

Issue of the periodical within the volume

7

Country of publishing house

CH - SWITZERLAND

Number of pages

34

Pages from-to

nestrankovano

UT code for WoS article

000781842400001

EID of the result in the Scopus database

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