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Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion.

ABSTRACT: BACKGROUND AND PURPOSE:A hallmark of tumour invasion is breakdown of the extracellular matrix due to dysregulation of the matrix metalloproteinase (MMP) system. While our understanding of how this is regulated by kinase signalling pathways is well established, its counter-regulation by protein phosphatases (PP) is poorly understood. Therefore, we investigated the effect of PP inhibition on markers of extracellular remodelling and how PP2A activity modulated MMP-9 abundance and function of Hep3B cells. EXPERIMENTAL APPROACH:Cells were exposed to okadaic acid (OA), tautomycetin and cyclosporin A, and the expression profile determined using PCR. Effects of OA and a protein inhibitor of PP2A, CIP2A, on MMP-9 abundance, PP2A activity and cell migration were investigated using ELISA, promoter constructs, siRNA knockdown and transwell migration assays. KEY RESULTS:OA increased expression and abundance of MMP-9 and the tissue inhibitor of MMP, TIMP-1, without affecting other MMPs, TIMPs and ADAMs. The effect on MMP-9 was mimicked by CIP2A overexpression and knockdown of the PPP2CA catalytic, but not PPP2R1A scaffolding, subunit. Cyclosporin A and PPP1CA silencing did not alter MMP-9 expression, while tautomycetin transiently increased it. Mutation of AP-1, but not NF-?B, binding sites inhibited OA-mediated MMP-9 transcriptional activity. OA and CIP2A decreased PP2A activity and increased cell migration. CONCLUSION AND IMPLICATIONS:OA increased MMP-9 by decreasing PP2A activity and PP2Ac, through AP-1 binding sites on the MMP-9 promoter. The functional consequence of this and CIP2A overexpression was increased cell migration. Hence, PP2A inhibition induced a metastatic phenotype through alterations in MMP-9 in Hep3B cells.

SUBMITTER: Ward MP

PROVIDER: S-EPMC5406286 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion.

Ward M P MP Spiers J P JP

British journal of pharmacology 20170407 10

<h4>Background and purpose</h4>A hallmark of tumour invasion is breakdown of the extracellular matrix due to dysregulation of the matrix metalloproteinase (MMP) system. While our understanding of how this is regulated by kinase signalling pathways is well established, its counter-regulation by protein phosphatases (PP) is poorly understood. Therefore, we investigated the effect of PP inhibition on markers of extracellular remodelling and how PP2A activity modulated MMP-9 abundance and function o ...[more]

PMID: 28239848

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Project description:BackgroundInterleukin-33 (IL-33) is an effective inducer of pro-inflammatory cytokines regulating innate and adaptive immunity. Inflammation could be a double-edged sword, promoting or inhibiting tumour growth. To date, the roles and mechanisms of IL-33 in tumours remain controversial. Here, we examined the effect of exogenous IL-33 on the biological characteristics of hepatocellular carcinoma (HCC) and the possible mechanism of action.MethodsIn this study, IL-33 expression in the tissues of 69 HCC patients was detected and its relationship with prognosis was evaluated. After establishing a mouse HCC model and IL-33 treatment operation, the infiltration of splenic myeloid-derived suppressor (MDSCs), dendritic (DCs), regulatory T, and natural killer (NK) cells was detected by flow cytometry analysis, and the vascular density of the tumour tissues was detected by immunohistochemistry to reveal the mechanism of IL-33 in HCC proliferation. Finally, the Cancer Genome Atlas database was used to analyse Gene Ontology terms the and Kyoto Encyclopaedia of Genes and Genomes pathway. Moreover, the chi-square test, two-tailed unpaired Student's t-test, and multiple t-tests were performed using SPSS version 23.0 and GraphPad Prism 8.0 software.ResultsThe IL-33 expression level was negatively correlated with the overall survival of HCC patients, suggesting its potential clinical significance in the prognosis of HCC. We found that systemic IL-33 administration significantly promoted the tumour size in vivo. Furthermore, the IL-33-treated mice presented decreased frequencies of tumouricidal NK and CD69+ CD8+ T cells. After IL-33 treatment, the incidence of monocytic MDSCs and conventional DCs increased, while that of granulocytic MDSCs decreased. Moreover, IL-33 promoted the formation of intracellular neovascularization. Therefore, IL-33 accelerated HCC progression by increasing the accumulation of immunosuppressive cells and neovascularization formation. Finally, we found that the transcription of IL-33 was closely related to the PI3K-Akt and MAPK pathways in Gene Set Enrichment Analysis plots, which were involved in the tumourigenesis and pathogenesis of HCC.ConclusionsTaken together, IL-33 may be a key tumour promoter of HCC proliferation and tumourigenicity, an important mediator, and a potential therapeutic target for regulating HCC progression.

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Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion.

Publications

Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion.

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