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Gene expression profiling after RNA interference of CXCR4 in human ovarian cancer cell line IGROV-1.

ABSTRACT: In the past three years the role of inflammatory cytokines and chemokines in tumour promotion and progression has been intensively studied. The chemokine receptor CXCR4 and its ligand CXCL12 are commonly expressed in malignant cells from primary tumours, metastases and also in malignant cell lines. To investigate the biological significance of this receptor/ligand pair, we knocked-down CXCR4 expression in ovarian cancer cell line IGROV-1 using shRNA, and established stable cell lines. Using Affymetrix microarrays we compared in vitro gene expression in parental IGROV-1 and IGROV-Mock cells with two clones of IGROV-shCXCR4 cells. Gene Set Enrichment Analysis (GSEA) of those genes which were altered by RNA interference of CXCR4 revealed evidence for a cell autonomous signaling network involving CXCR4, TNF-a, IL6 and Notch pathways in ovarian cancer cells. Keywords: Affymetrix GeneChip Human Genome U133Plus 2.0

ORGANISM(S): Homo sapiens

PROVIDER: GSE13763 | GEO | 2008/11/29

SECONDARY ACCESSION(S): PRJNA110765

REPOSITORIES: GEO

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Project description:In colorectal cancer, increased expression of the CXC chemokine receptor 4 (CXCR4) has been shown to provoke metastatic disease due to the interaction with its ligand stromal cell-derived factor 1 (SDF-1). Recently, a second SDF-1 receptor, CXCR7, was found to enhance tumor growth in solid tumors. Albeit signaling cascades via SDF-1/CXCR4 have been intensively studied, the significance of the SDF-1/CXCR7-induced intracellular communication triggering malignancy is still only marginally understood. In tumor tissue of 52 colorectal cancer (CRC) patients, we observed that expression of CXCR7 and CXCR4 increased with tumor stage, tumor size, and lymph node infiltration. Asking whether activation of CXCR4 or CXCR7 might result in a similar expression pattern, we performed microarray expression analyses using lentivirally CXCR4- and/or CXCR7-overexpressing SW480 colon cancer cell lines with and without stimulation by SDF-1M-NM-1. Gene regulation via SDF-1M-NM-1/CXCR4 and SDF-1M-NM-1/CXCR7 was completely different and partly antidromic. Expressions of the differentially expressed genes AKR1C3, AXL, EGFR, IGFBP7, IL24, TNNC1, TRIP6 were confirmed by qPCR. Differentially regulated genes were assigned by GO to migration and lipid metabolic processes. Furthermore, using the in silico gene set enrichment analysis we showed for the first time that expressions of miR-217 and miR-218 were increased in CXCR4 and reduced in CXCR7 cells after stimulation with SDF-1M-NM-1. As expected, their putative target mRNAs were inversely expressed. Functional assays exerted that exposure to SDF-1M-NM-1 resulted in strongly amplified invasiveness and chemosensitivity of CXCR4-expressing cells. CXCR7 overexpression led to reduced invasiveness which could only be marginally increased by SDF-1M-NM-1. The CXCR4 antagonist plerixafor significantly reduced invasiveness of CXCR4-overexpressing cells only. Similarly, compared to control cells, CXCR4 cells showed increased sensitivity against 5-FU, while CXCR7 cells were more chemoresistant. These opposing results for CXCR4- or CXCR7-overexpressing colon carcinoma cells demand an unexpected attention in the clinical application of chemokine receptor antagonists like Plerixafor. 24 samples

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Gene expression profiling after RNA interference of CXCR4 in human ovarian cancer cell line IGROV-1.

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