The IL-8-Regulated Chemokine Receptor CXCR7 Stimulates EGFR Signaling to Promote Prostate Cancer Growth
The IL-8-Regulated Chemokine Receptor CXCR7 Stimulates EGFR Signaling to Promote Prostate Cancer Growth
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DOI：
10.1158/0008-5472.can-10-2769
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发表时间：
2011-05-01
期刊：
影响因子：
11.2
通讯作者：
Lokeshwar, Bal L.
中科院分区：
文献类型：
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作者：
Singh, Rajendra Kumar;Lokeshwar, Bal L.
结合配体CXCL 11和CXCL 12（SDF-1a）的促炎趋化因子受体CXCR 7在多种人类癌症中升高，但其功能尚不清楚，因为它不会引发经典的趋化因子受体信号传导。在这里，我们报告说，癌前细胞因子IL-8（白细胞介素-8）上调CXCR 7的表达沿着配体非依赖性功能的CXCR 7，促进人类前列腺癌细胞（CaP细胞）的生长和增殖。在细胞培养中，异位表达或添加IL-8在mRNA和蛋白质产生水平选择性增加CXCR 7的表达。相反，抑制IL-8信号传导消除了IL-8上调CXCR 7的能力。RNAi介导的CaP细胞CXCR 7基因敲低可导致多种抗肿瘤效应，包括细胞增殖降低、细胞周期停滞在G（1）期以及参与G（1）至S期进展的蛋白表达降低。相反，向CaP细胞添加CXCR 7配体SDF-1a和CXCL 11不影响细胞增殖。正常前列腺细胞中CXCR 7的过度表达以与磷酸化EGFR（表皮生长因子受体; pY 1110）和磷酸化ERK 1/2水平增加相关的方式增加其增殖。值得注意的是，免疫共沉淀研究建立了CXCR 7与EGFR的物理联系，将CXCR 7介导的细胞增殖与EGFR活化联系起来。与这些发现一致，CXCR 7缺失的CaP肿瘤比对照肿瘤生长更慢，表达VEGF、细胞周期蛋白D1和p-EGFR的肿瘤相关表达降低。总之，这些结果揭示了CXCR 7促进配体非依赖性生长的新机制及其与促炎因子IL-8在前列腺癌中的协同调节。Cancer Res; 71（9）; 3268-77. (C)2011年AACR。
The proinflammatory chemokine receptor CXCR7 that binds the ligands CXCL11 and CXCL12 (SDF-1a) is elevated in a variety of human cancers, but its functions are not understood as it does not elicit classical chemokine receptor signaling. Here we report that the procancerous cytokine IL-8 (interleukin-8) upregulates CXCR7 expression along with ligand-independent functions of CXCR7 that promote the growth and proliferation of human prostate cancer cells (CaP cells). In cell culture, ectopic expression or addition of IL-8 selectively increased expression of CXCR7 at the level of mRNA and protein production. Conversely, suppressing IL-8 signaling abolished the ability of IL-8 to upregulate CXCR7. RNAi-mediated knockdown of CXCR7 in CaP cells caused multiple antitumor effects, including decreased cell proliferation, cell-cycle arrest in G(1) phase, and decreased expression of proteins involved in G(1) to S phase progression. In contrast, addition of the CXCR7 ligand SDF-1a and CXCL11 to CaP cells did not affect cell proliferation. Over expression of CXCR7 in normal prostate cells increased their proliferation in a manner associated with increased levels of phospho-EGFR (epidermal growth factor receptor; pY1110) and phospho-ERK1/2. Notably, coimmunoprecipitation studies established a physical association of CXCR7 with EGFR, linking CXCR7-mediated cell proliferation to EGFR activation. Consistent with these findings, CXCR7-depleted CaP tumors grew more slowly than control tumors, expressing decreased tumor-associated expression of VEGF, cyclin D1, and p-EGFR. Together, these results reveal a novel mechanism of ligand-independent growth promotion by CXCR7 and its coregulation by the proinflammatory factor IL-8 in prostate cancer. Cancer Res; 71(9); 3268-77. (C) 2011 AACR.