Background and Aims: The molecular mechanisms underlying the development and progression of HCC remain poorly understood. The MAP kinase ERK5 has been implicated in tumor development. The goal of this study was to evaluate the relevance of this pathway ERK5 in HCC biology and to establish its downstream targets. Methods: In Huh-7 and HepG2, ERK5 was silenced by siRNA transfection or with lentiviral vectors encoding specific shRNA. The specific ERK5 inhibitor XMD8–92 was also used. In vivo development of HCC was evaluated using a xenograft model with Huh-7 in nude mice. Results: In vitro , ERK5 silencing or inhibition caused growth arrest of HCC cells, affecting the G1/S transition. This phenotype was associated with an increased expression of p27Kip, a negative regulator of cell cycle progression. Upon ERK5 knockdown, expression of c-Rel, a member of the NF-kappaB family required for hepatocyte proliferation, was markedly downregulated. In a mouse model of HCC xenograft, ERK5 silencing or administration of XMD8–92 significantly decreased tumor volume. These effects were associated with reduced cell proliferation, as indicated by lower BrdU incorporation. Upon reduction of ERK5 levels of activity in vivo , levels of c-Rel and of c-Jun, a proto-oncogene essential for cell proliferation, were reduced. Expression of MEF2, a known target in the ERK5 pathway, was also inhibited. Conclusions: We found that ERK5 regulates cell proliferation in HCC in vivo and in vitro , affecting the expression of different oncogenic targets, including c-Rel, which we identify for the first time as a target of ERK5

c-Rel AND p27Kip ARE DOWNSTREAM TARGETS OF ERK5 IN HEPATOCELLULAR CARCINOMA (HCC) IN VIVO AND IN VITRO / G. Di Maira; E. Rovida; N. Navari; S. Cannito; P. Dello Sbarba; M. Parola; F. Marra. - In: JOURNAL OF HEPATOLOGY. - ISSN 0168-8278. - STAMPA. - (2014), pp. S97-S98. [10.1016/S0168-8278(14)60257-9]

c-Rel AND p27Kip ARE DOWNSTREAM TARGETS OF ERK5 IN HEPATOCELLULAR CARCINOMA (HCC) IN VIVO AND IN VITRO

DI MAIRA, GIOVANNI;ROVIDA, ELISABETTA;NAVARI, NADIA;DELLO SBARBA, PERSIO;MARRA, FABIO
2014

Abstract

Background and Aims: The molecular mechanisms underlying the development and progression of HCC remain poorly understood. The MAP kinase ERK5 has been implicated in tumor development. The goal of this study was to evaluate the relevance of this pathway ERK5 in HCC biology and to establish its downstream targets. Methods: In Huh-7 and HepG2, ERK5 was silenced by siRNA transfection or with lentiviral vectors encoding specific shRNA. The specific ERK5 inhibitor XMD8–92 was also used. In vivo development of HCC was evaluated using a xenograft model with Huh-7 in nude mice. Results: In vitro , ERK5 silencing or inhibition caused growth arrest of HCC cells, affecting the G1/S transition. This phenotype was associated with an increased expression of p27Kip, a negative regulator of cell cycle progression. Upon ERK5 knockdown, expression of c-Rel, a member of the NF-kappaB family required for hepatocyte proliferation, was markedly downregulated. In a mouse model of HCC xenograft, ERK5 silencing or administration of XMD8–92 significantly decreased tumor volume. These effects were associated with reduced cell proliferation, as indicated by lower BrdU incorporation. Upon reduction of ERK5 levels of activity in vivo , levels of c-Rel and of c-Jun, a proto-oncogene essential for cell proliferation, were reduced. Expression of MEF2, a known target in the ERK5 pathway, was also inhibited. Conclusions: We found that ERK5 regulates cell proliferation in HCC in vivo and in vitro , affecting the expression of different oncogenic targets, including c-Rel, which we identify for the first time as a target of ERK5
2014
G. Di Maira; E. Rovida; N. Navari; S. Cannito; P. Dello Sbarba; M. Parola; F. Marra
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/966209
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