MKP-4 Suppresses Hepatocarcinogenesis by Targeting ERK1/2 Pathway

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2019 Mar 30

PMID 30923463

Citations 8

Authors

Zhongyi Shen

Chengliang Zhang

Lishuai Qu

Cuihua Lu

Mingbing Xiao

Runzhou Ni

Jinxia Liu

Affiliations

Soon will be listed here.

Abstract

Background: Mitogen-activated protein kinase phosphatases-4 (MKP-4) is reported to exert a prognostic merit in hepatocarcinogenesis. However, the underlying molecular mechanisms have not been clearly defined.

Methods: Immunoprecipitation-mass spectrometry (IP-MS) approach was used to identify interactive proteins with MKP-4. Western blot and immunohistochemistry were employed to detect proteins in HCC tissues. Cell counting kit-8, colony formation, Edu incorporation and sphere formation assays were performed to investigate functions of MKP-4/ERK1/2 interaction. Tumor xenografts in nude mice were used to determine effects in vivo.

Results: Extracellular signal-regulated kinase 1 and 2 (ERK1/2) were identified as binding partners of MKP-4. Knockdown of MKP-4 increased cell proliferation and cancer stem cell (CSC) traits while upregulation of MKP-4 or pre-incubation with ERK1/2 inhibition reversed these effects. Mechanistically MKP-4 negatively regulated phosphorylation of ERK1/2 and reduced expressions of CyclinD1 and c-Myc. Both xenograft tumor models and clinical analysis of HCC patients indicated that lower expression of MKP-4 and higher expressions of ERK1/2 were associated with worse prognosis.

Conclusions: MKP-4-mediated dephosphorylation of ERK1/2 might serve as a novel tumor-suppressive mechanism and provide a potential therapy for HCC.

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