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

Autor: Tonon F; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy., Cemazar M; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia.; Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310 Izola, Slovenia., Kamensek U; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia., Zennaro C; Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume 447, I-34149 Trieste, Italy., Pozzato G; Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital, Strada di Fiume 447, I-34149 Trieste, Italy., Caserta S; Department of Chemical, Materials and Industrial Production Engineering, University of Naples 'Federico II', Piazzale V. Tecchio 80, I-80125 Naples, Italy.; CEINGE Advanced Biotechnologies, via Gaetano Salvatore, 486, I-80145 Napoli, Italy., Ascione F; Department of Chemical, Materials and Industrial Production Engineering, University of Naples 'Federico II', Piazzale V. Tecchio 80, I-80125 Naples, Italy., Grassi M; Department of Engineering and Architecture, University of Trieste, Via Valerio 6/A, I-34127 Trieste, Italy., Guido S; Department of Chemical, Materials and Industrial Production Engineering, University of Naples 'Federico II', Piazzale V. Tecchio 80, I-80125 Naples, Italy.; CEINGE Advanced Biotechnologies, via Gaetano Salvatore, 486, I-80145 Napoli, Italy., Ferrari C; Department of Clinic-Surgical Sciences, Laboratory of Experimental Surgery and Animal Facility, University of Pavia, Via Ferrata 9, I-27100 Pavia, Italy., Cansolino L; Department of Clinic-Surgical Sciences, Laboratory of Experimental Surgery and Animal Facility, University of Pavia, Via Ferrata 9, I-27100 Pavia, Italy., Trotta F; Department of General Surgery, Maggiore Hospital, Largo Donatori del Sangue 1, I-26900 Lodi, Italy., Kuzmanov BG; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000 Ljubljana, Slovenia., Forte G; International Clinical Research Center (ICRC) of St Anne's University Hospital, CZ-65691 Brno, Czech Republic., Martino F; International Clinical Research Center (ICRC) of St Anne's University Hospital, CZ-65691 Brno, Czech Republic., Perrone F; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy.; Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK., Bomben R; Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero a Cura a Carattere Scientifico IRCCS, 33081 Aviano, Italy., Gattei V; Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero a Cura a Carattere Scientifico IRCCS, 33081 Aviano, Italy., Elvassore N; Industrial Engineering Department, University of Padova, Via Francesco Marzolo, 9, I-35131 Padova, Italy., Murano E; Nealys SRL, Via Flavia 23/1, I-34148 Trieste, Italy., Truong NH; Stem Cell Research and Application Laboratory, VNUHCM, University of Science, Ho Chi Minh City 72711, Vietnam., Olson M; Department of Chemistry and Biology, X University, MaRS Discovery District, West Tower 661 University Avenue, Toronto, ON M5G 1M1, Canada., Farra R; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy., Grassi G; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy., Dapas B; Department of Life Sciences, Cattinara University Hospital, Trieste University, Strada di Fiume 447, I-34149 Trieste, Italy.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2022 Mar 23; Vol. 14 (7). Date of Electronic Publication: 2022 Mar 23.
DOI: 10.3390/cancers14071630
Abstrakt: 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.
Databáze: MEDLINE
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