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Downregulation of GRK5 hampers the migration of breast cancer cells.

ABSTRACT: Sunitinib is a multispecific kinase inhibitor and one of its targets is the kinase GRK5, which is regulating a multitude of G protein-coupled receptors (GPCRs). In this study we demonstrate that a decreased GRK5 expression induced by knock-down experiments or sunitinib treatment hampers the migration of cancer cell lines. A proteomic analysis revealed many pathways related to cell migration which were down regulated upon the GRK5 knock-down. Furthermore, we found in MDA-MB-231 breast cancer cells that the inhibition of migration is mediated by the GPCR gastrin releasing peptide receptor (GRPR) leading to a reduced expression of migration regulating downstream targets like CDC42 and ROCK1. An in silico Kaplan Meier analysis revealed that GRK5 and GRPR overexpression reduces the distant metastasis free survival in triple-negative breast cancer (TNBC) patients. Thus, we suggest a novel anti-migratory effect of impaired GRK5 expression which induces a negative feedback loop on GRPR signalling.

SUBMITTER: Sommer AK

PROVIDER: S-EPMC6820534 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Downregulation of GRK5 hampers the migration of breast cancer cells.

Sommer Ann-Katrin AK Falcenberg Mathias M Ljepoja Bojan B Fröhlich Thomas T Arnold Georg J GJ Wagner Ernst E Roidl Andreas A

Scientific reports 20191029 1

Sunitinib is a multispecific kinase inhibitor and one of its targets is the kinase GRK5, which is regulating a multitude of G protein-coupled receptors (GPCRs). In this study we demonstrate that a decreased GRK5 expression induced by knock-down experiments or sunitinib treatment hampers the migration of cancer cell lines. A proteomic analysis revealed many pathways related to cell migration which were down regulated upon the GRK5 knock-down. Furthermore, we found in MDA-MB-231 breast cancer cell ...[more]

PMID: 31664083

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Project description:BackgroundThe involvement of miRNAs in the regulation of fundamental cellular functions has placed them at the fore of ongoing investigations into the processes underlying carcinogenesis. MiRNA expression patterns have been shown to be dysregulated in numerous human malignancies, including breast cancer, suggesting their probable involvement as novel classes of oncogenes or tumour suppressor genes. The identification of differentially expressed miRNAs and elucidation of their functional roles may provide insight into the complex and diverse molecular mechanisms of tumorigenesis. MiR-183 is located on chromosome 7q32 and is part of a miRNA family which are dysregulated in numerous cancers. The aims of this study were to further examine the expression and functional role of miR-183 in breast cancer.MethodsMiR-183 expression was quantitated in primary breast tumours, tumour associated normal tissue and breast cancer cell lines using RQ-PCR. Gain of function analysis was performed in breast cancer cells using pre-miR-183 and the effect of miR-183 overexpression on cell viability, proliferation, apoptosis and migration was examined. Customized Taqman Low Density Arrays (TLDA) were used to identify dysregulated genes in breast cancer cells transfected with pre-miR-183.ResultsWe demonstrate that miR-183 is dysregulated in breast cancer and expression correlates with estrogen receptor and HER2/neu receptor expression. Induced overexpression of miR-183 inhibited migration of breast cancer cells. This finding was substantiated by RQ-PCR of mRNA from cells overexpressing miR-183 which showed dysregulation of several migration and invasion related genes. Specifically, the VIL2-coding protein Ezrin was confirmed as a target of miR-183 and downregulation of this protein was confirmed with immunocytochemistry.ConclusionsThese findings indicate that miR-183 targets VIL2 and may play a central role in the regulation of migration and metastasis in breast cancer. Consequently, this miRNA may present an attractive target for therapeutic intervention.

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Downregulation of GRK5 hampers the migration of breast cancer cells.

Publications

Downregulation of GRK5 hampers the migration of breast cancer cells.

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