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.
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DOI：
10.1186/1476-4598-13-198
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发表时间：
2014-08-28
期刊：
影响因子：
37.3
通讯作者：
Lokeshwar BL
中科院分区：
文献类型：
--
作者：
Salazar N;Muñoz D;Kallifatidis G;Singh RK;Jordà M;Lokeshwar BL
最近的进展揭示了趋化因子及其受体在肿瘤生长、化疗后生存和器官特异性转移中的显着贡献。CXC趋化因子受体-7（CXCR 7）是最新发现的与癌症有关的趋化因子受体。虽然在乳腺癌细胞系和肿瘤组织中过表达，但其在乳腺癌（BrCa）生长和转移中的作用机制尚不清楚。在其他癌症中的研究表明CXCR 7参与细胞增殖、抗凋亡活性和细胞-细胞粘附。本研究旨在研究CXCR 7的表达模式及其在乳腺癌生长信号调节中的作用。使用真实的时间定量PCR（q-PCR）、增殖测定、免疫组织化学和免疫印迹在代表性细胞系中研究CXCR 7在BrCa细胞增殖中的贡献。在CXCR 7特异性cDNA和siRNA转染后检查表型变化，并通过q-PCR监测表达水平。此外，CXCR 7与表皮生长因子受体（EGFR）的关联及其活性的调节在人BrCa细胞和组织中通过蛋白质印迹、免疫荧光和原位邻位连接测定进行了研究。CXCR 7在雌激素受体（ER）阳性和阴性BrCa细胞系中均表达。CXCR 7在正常乳腺组织中也不均匀表达，在ER +癌组织中表达程度更高。通过RNA干扰在MCF 7 BrCa细胞中消耗CXCR 7降低增殖并引起细胞周期停滞。此外，邻近连接测定（PLA）揭示了CXCR 7与EGFR在癌组织和癌细胞系中的共定位。CXCR 7耗竭降低EGF刺激后酪氨酸1110处的磷酸化EGFR水平，也降低ERK 1/2的磷酸化，表明对MCF 7细胞中促有丝分裂信号传导的潜在直接影响。使用siRNA敲低EGFR过表达细胞中的β-arrestin 2，我们能够几乎耗尽CXCR 7-EGFR共定位事件，表明β-arrestin 2作为支架在EGF刺激后增强EGFR的CXCR 7依赖性活化。这些结果表明CXCR 7与EGFR偶联以调节BrCa细胞的增殖，并表明CXCR 7在BrCa生长中的重要配体非依赖性作用。因此，CXCR 7-EGFR轴是乳腺癌治疗的有希望的靶点。本文的在线版本（doi：10.1186/1476-4598-13-198）包含补充材料，可供授权用户使用。
Recent 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. The 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. CXCR7 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. These 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. The 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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影响因子：
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作者：
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Luker, G. D.