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The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma
  1. Elisabetta Rovida1,
  2. Giovanni Di Maira2,
  3. Ignazia Tusa1,
  4. Stefania Cannito3,
  5. Claudia Paternostro3,
  6. Nadia Navari2,
  7. Elisa Vivoli2,
  8. Xianming Deng4,5,
  9. Nathanael S Gray4,
  10. Azucena Esparís-Ogando6,
  11. Ezio David7,
  12. Atanasio Pandiella6,
  13. Persio Dello Sbarba1,
  14. Maurizio Parola3,
  15. Fabio Marra2
  1. 1Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università di Firenze, Italy
  2. 2Dipartimento di Medicina Sperimentale e Clinica Università di Firenze, Italy
  3. 3Dipartimento di Medicina e Oncologia Sperimentali, Università di Torino, Italy
  4. 4Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
  5. 5School of Life Sciences, Xiamen University, Xiamen, Fujian, China
  6. 6Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Spain
  7. 7Pathology Unit, Ospedale S. Giovanni Battista, Torino, Italy
  1. Correspondence to Professor Fabio Marra, Dipartimento di Medicina Sperimentale e Clinica, Università di Firenze, Largo Brambilla 3, Florence I-50134, Italy; fabio.marra{at}unifi.it and Dr Elisabetta Rovida Dipartimento di Scienze Biomediche, Sperimentali e Cliniche, Università di Firenze, Largo Brambilla 3, Florence I-50134, Italy; elisabetta.rovida@unifi.it

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.

Design 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.

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