MKP-4 suppresses hepatocarcinogenesis by targeting ERK1/2 pathway

Cancer Cell International

Chengliang Zhang¹  Lishuai Qu²  Jinxia Liu²  Mingbing Xiao²  Runzhou Ni²  Zhongyi Shen²  Cuihua Lu² 

[1] Clinical Medicine Medical College, Nantong University;Department of Gastroenterology, Affiliated Hospital of Nantong University;

关键词: MKP-4;    ERK1/2;    Hepatocellular carcinoma;    Phosphorylation;    Prognosis;   

DOI  :  10.1186/s12935-019-0776-3

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown