ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry

Zen, Keika; Yasui, Kohichiroh; Nakajima, Tomoaki; Zen, Yoh; Zen, Kan; Gen, Yasuyuki; Mitsuyoshi, Hironori; Minami, Masahito; Mitsufuji, Shoji; Tanaka, Shinji; Itoh, Yoshito; Nakanuma, Yasuni; Taniwaki, Masafumi; Arii, Shigeki; Okanoue, Takeshi; Yoshikawa, Toshikazu

doi:10.1002/gcc.20624

Cited by 58 publications

(81 citation statements)

References 48 publications

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“…Moreover, the MAPK7 gene, encoding for ERK5, was found to be amplified in human HCC specimens and cell lines. 9,10 Nonetheless, limited functional information on its possible role in HCC has been reported. Using two wellestablished cellular models, our in vitro data indicate that inhibition of the ERK5 pathway reduces the proliferation of Huh-7 and HepG2 cells, and that ERK5 activity is necessary for progression in the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

Rovida¹,

Maira²,

Cannito³

et al. 2014

European Journal of Cancer

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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. ResultsIn 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. Significance of this study

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Section: Discussionmentioning

confidence: 99%

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

Rovida¹,

Maira²,

Cannito³

et al. 2014

European Journal of Cancer

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“…Despite remarkable advances already achieved in the diagnosis and treatment of hepatocellular carcinoma, it still has the secondhighest mortality rate [23,[74][75][76]. Most hepatocellular carcinomas develop as a result of chronic liver disease, which, in combination with several other factors, such as inflammation, oxidative stress, and a hypoxic microenvironment, typically occurring in the liver, can have a role in tumour initiation, progression, and metastasis, importantly contributing to poorer prognosis and hampered therapeutics.…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

Simões

Rodrigues

Borralho

2016

Drug Discovery Today

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“…Zen et al (39) reported that downregulation of MAPK7 by small interfering RNA suppressed the growth of SNU449 cells, which comprise the HCC cell line with the greatest amplification and overexpression of MAPK7. ERK5, which is phosphorylated during the G2/M phases of the cell cycle, may regulate entry into mitosis in SNU449 cells (40).…”

Section: Mir-143 Downregulates the Expression Of Erk5 And C-fosmentioning

confidence: 99%

miR-143 is associated with proliferation and apoptosis involving ERK5 in HeLa cells

et al. 2016

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Abstract. Inappropriate expression of microRNA (miR) is strongly associated with carcinogenesis. miR-143 was reported to be one of the most prominent miRs implicated in the genesis and progression of human cancer. However, its correlation with cell proliferation and apoptosis in cervical cancer remains to be fully elucidated. In the present study, it was demonstrated that miR-143 is able to suppress the proliferation of cervical cancer HeLa cells and induce cell apoptosis in a time-and dose-dependent manner. The present study also investigated the potential targets of miR-143, extracellular-signal-regulated kinase 5 (ERK5) and its downstream substrate oncoprotein c-Fos, both of which are involved in cell proliferation and apoptosis. Upon increasing the miR-143 level, the ERK5 and c-Fos protein expression was significantly decreased without the effect of ERK5 transcription. Therefore, miR-143 is able to suppress cell proliferation and induce apoptosis in HeLa cells, potentially through negative regulation of ERK5 at its post-transcriptional stage.

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ERK5 is a target for gene amplification at 17p11 and promotes cell growth in hepatocellular carcinoma by regulating mitotic entry

Cited by 58 publications

References 48 publications

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

786: The mitogen-activated protein kinase ERK5 regulates the development and growth of hepatocellular carcinoma

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

miR-143 is associated with proliferation and apoptosis involving ERK5 in HeLa cells

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