CXCR7 participates in CXCL12-induced CD34+ cell cycling through β-arrestin–dependent Akt activation

Torossian, Frédéric; Anginot, Adrienne; Chabanon, A.; Clay, Denis; Guerton, Bernadette; Desterke, Christophe; Boutin, Laetitia; Marullo, Stéfano; Scott, Mark G. H.; Lataillade, Jean‐Jacques; Bousse‐Kerdilès, Marie‐Caroline Le

doi:10.1182/blood-2013-05-500496

Cited by 42 publications

(41 citation statements)

References 43 publications

(75 reference statements)

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“…The arrestin scaffolds may serve as adapter molecules to assemble multi-protein complexes ultimately leading to receptor internalization, recycling back to the plasma membrane, and downstream signaling events, including ERK1/2 (extracellular signal-regulated kinases) activation [9–11]. Arrestins may also shuttle between the cell nucleus and cytoplasm [12]. This process is not fully elucidated for CXCR7.…”

Section: Introductionmentioning

confidence: 99%

The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

et al. 2014

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BackgroundRecent advances have revealed a significant contribution of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. The CXC chemokine receptor-7 (CXCR7) is the latest chemokine receptor implicated in cancer. Although over expressed in breast cancer cell lines and tumor tissues, its mechanism of action in breast cancer (BrCa) growth and metastasis is unclear. Studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. The present study was initiated to examine the pattern of CXCR7 expression and its role in regulation of growth signaling in breast cancer.MethodsThe contribution of CXCR7 in BrCa cell proliferation was investigated in representative cell lines using real time quantitative PCR (q-PCR), proliferation assays, immunohistochemistry and immunoblotting. Phenotypic changes were examined after CXCR7 specific cDNA and siRNA transfection and expression levels were monitored by q-PCR. Further, the association of CXCR7 with epidermal growth factor receptor (EGFR) and modulation of its activity were investigated by western blotting, immunofluorescence, and in-situ proximity ligation assays in human BrCa cells and tissues.ResultsCXCR7 was expressed in both, estrogen receptor (ER) positive and negative BrCa cell lines. CXCR7 was also expressed unevenly in normal breast tissues and to a much higher extent in ER + cancer tissues. Depletion of CXCR7 in MCF7 BrCa cells by RNA interference decreased proliferation and caused cell cycle arrest. Further, proximity ligation assay (PLA) revealed colocalization of CXCR7 with EGFR in cancer tissues and cancer cell lines. CXCR7 depletion reduced levels of phospho-EGFR at Tyrosine1110 after EGF-stimulation and also reduced phosphorylation of ERK1/2, indicating a potentially direct impact on mitogenic signaling in MCF7 cells. Using siRNA to knockdown β-arrestin2 in cells with EGFR over expression we were able to nearly deplete the CXCR7-EGFR colocalization events, suggesting that β-arrestin2 acts as a scaffold to enhance CXCR7 dependent activation of EGFR after EGF stimulation.ConclusionsThese results demonstrate coupling of CXCR7 with EGFR to regulate proliferation of BrCa cells and suggest an important ligand-independent role of CXCR7 in BrCa growth. Thus, the CXCR7-EGFR axis is a promising target for breast cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-198) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

et al. 2014

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“…8 The activity of CXCL12 is mediated by binding of the chemokine to its receptors (CXCR4 and CXCR7) on circulating hematopoietic cells. 9,10 Experimental evidence has accumulated on the crucial role of the CXCL12/CXCR4 axis in the bone marrow niche. Sugijama et al demonstrated that abrogation of CXCL12/CXCR4 signaling is associated with a reduction in HSPC numbers.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

et al. 2014

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The chemokine CXCL12 regulates the interaction between hematopoietic stem and progenitor cells and bone marrow stromal cells. Although its relevance in the bone marrow niche is well recognized, the regulation of CXCL12 by microRNA is not completely understood. We transfected a library of 486 microRNA in the bone marrow stromal cell line SCP-1 and studied the expression of CXCL12. Twenty-seven microRNA were shown to downregulate expression of CXCL12. Eight microRNA (miR-23a, 130b, 135, 200b, 200c, 216, 222, and 602) interacted directly with the 3´UTR of CXCL12. Next, we determined that only miR-23a is predicted to bind to the 3´UTR and is strongly expressed in primary bone marrow stromal cells. Modulation of miR-23a changes the migratory potential of hematopoietic progenitor cells in co-culture experiments. We discovered that TGFB1 mediates its inhibitory effect on CXCL12 levels by upregulation of miR-23a. This process was partly reversed by miR-23a molecules. Finally, we determined an inverse expression of CXCL12 and miR-23a in stromal cells from patients with myelodysplastic syndrome indicating that the interaction has a pathophysiological role. Here, we show for the first time that CXCL12-targeting miR23a regulates the functional properties of the hematopoietic niche. MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nproteases. 11,12 Furthermore, CXCL12 expression can be transcriptionally modulated by a variety of cytokines and growth factors, namely transforming growth factor-beta 1 (TGFB1). TGFB1 has a negative growth effect on HSPC which is mediated, in part, by the regulation of CXCL12 arising from stromal cells. 13 Thus, engraftment and response to cytotoxic drugs may vary according to CXCL12 levels provided by niche cells. 14,15 Recently, Pillai et al. suggested that CXCL12 can also be regulated by microRNA (miRNA) in human marrow stromal cells. 16 There are more than 1000 miRNA which form 1-2% of the human genome. Approximately half of human structural genes are predicted to be under miRNA control. In animals, miRNA act by targeting the 3ú ntranslated region (UTR) of genes with the consequence of repressing output of the respective protein. A classical switch interaction is used to avoid protein expression in a particular cell type, whereas tuning interactions are needed to supply the cell with the optimal level of protein. 17 In the hematopoietic system, CXCL12 must be fine-tuned in response to differing physiological requirements.We, therefore, decided to study the interaction of CXCL12 and miRNA by applying a strategy of overexpression of a library to reveal the various miRNA responsible for CXCL12 regulation in primary human bone marrow stromal cells (hBMSC). Moreover, we mapped expression of candidate miRNA in primary hBMSC to understand their physiological function in fine tuning CXCL12 expression in the hematopoietic niche. Methods Cell linesHS5, HS27, HL60, K562, KG1a, and HeLa cell lines were ob...

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“…From these results we concluded that the HSC potential of the Tarnowski et al, 2010;Torossian et al, 2014). First trimester CD34 ++ CD45 low chorion cells expressed low levels of CXCR7 (ACKR3) and no detectable CD193 (CCR3) and CD195 (CCR5), but expression of the receptors increased in second trimester samples (Fig.…”

Section: Sorted Cd34mentioning

confidence: 80%

“…CD195 is expressed at higher levels on cord blood HSCs than on those obtained from BM or mobilized to peripheral blood (Rosu-Myles et al, 2000). CXCR7, another CXCL12 receptor (Tarnowski et al, 2010), cooperates with CD184 in enhancing the effects of CXCL12 on cell cycling, survival and proliferation of CD34 + cells from peripheral blood (Torossian et al, 2014). In addition, CD34 + cells from umbilical cord blood express CD193 (Lamkhioued et al, 2003), and CD191 expression by CD34 + cells in cord blood confers superior engraftment of immunodeficient mice (de Wynter et al, 2001 .…”

Section: Discussionmentioning

confidence: 99%

The human chorion contains definitive hematopoietic stem cells from the fifteenth week of gestation

et al. 2017

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We examined the contribution of the fetal membranes, amnion and chorion, to human embryonic and fetal hematopoiesis. A population of cells displaying a hematopoietic progenitor phenotype (CD34 ++ CD45 low ) of fetal origin was present in the chorion at all gestational ages, associated with stromal cells or near blood vessels, but was absent in the amnion. Prior to 15 weeks of gestation, these cells lacked hematopoietic in vivo engraftment potential. Differences in the chemokine receptor and β1 integrin expression profiles of progenitors between the first and second trimesters suggest that these cells had gestationally regulated responses to homing signals and/or adhesion mechanisms that influenced their ability to colonize the stem cell niche. Definitive hematopoietic stem cells, capable of multilineage and long-term reconstitution when transplanted in immunodeficient mice, were present in the chorion from 15-24 weeks gestation, but were absent at term. The second trimester cells also engrafted secondary recipients in serial transplantation experiments. Thus, the human chorion contains functionally mature hematopoietic stem cells at mid-gestation.

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CXCR7 participates in CXCL12-induced CD34+ cell cycling through β-arrestin–dependent Akt activation

Cited by 42 publications

References 43 publications

The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation

MicroRNA-23a mediates post-transcriptional regulation of CXCL12 in bone marrow stromal cells

The human chorion contains definitive hematopoietic stem cells from the fifteenth week of gestation

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