title: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma.
abstract: OBJECTIVE
  The extracellular signal-regulated kinase 5 (ERK5 or BMK1) is involved in tumour development. The ERK5 gene may be amplified in hepatocellular carcinoma (HCC), but its biological role has not been clarified. In this study, we explored the role of ERK5 expression and activity in HCC in vitro and in vivo.
  
  
  METHODS
  ERK5 expression was evaluated in human liver tissue. Cultured HepG2 and Huh-7 were studied after ERK5 knockdown by siRNA or in the presence of the specific pharmacological inhibitor, XMD8-92. The role of ERK5 in vivo was assessed using mouse Huh-7 xenografts.
  
  
  RESULTS
  In tissue specimens from patients with HCC, a higher percentage of cells with nuclear ERK5 expression was found both in HCC and in the surrounding cirrhotic tissue compared with normal liver tissue. Inhibition of ERK5 decreased HCC cell proliferation and increased the proportion of cells in G0/G1 phase. These effects were associated with increased expression of p27 and p15 and decreased CCND1. Treatment with XMD8-92 or ERK5 silencing prevented cell migration induced by epidermal growth factor or hypoxia and caused cytoskeletal remodelling. In mouse xenografts, the rate of tumour appearance and the size of tumours were significantly lower when Huh-7 was silenced for ERK5. Moreover, systemic treatment with XMD8-92 of mice with established HCC xenografts markedly reduced tumour growth and decreased the expression of the proto-oncogene c-Rel.
  
  
  CONCLUSIONS
  ERK5 regulates the biology of HCC cells and modulates tumour development and growth in vivo. This pathway should be investigated as a possible therapeutic target in HCC.
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica Università di Firenze, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Maira
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Italy.
authors.forename: Ignazia
authors.initials: I
authors.lastname: Tusa
authors.affiliation: Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cannito
authors.affiliation: Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Paternostro
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica Università di Firenze, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Navari
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica Università di Firenze, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Vivoli
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain.
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.affiliation: Pathology Unit, Ospedale S. Giovanni Battista, Torino, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: David
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain.
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Italy.
authors.forename: Persio
authors.initials: P
authors.lastname: Dello Sbarba
authors.affiliation: Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica Università di Firenze, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics*; D009368:Neoplasm Transplantation; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000032:analysis; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D048054:Mitogen-Activated Protein Kinase 7