Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami-Miller School of Medicine, Miami, FL, USA.
Georgia Cancer Center, Augusta University, Augusta, GA, USA.
Sci Rep. 2017 Jun 8;7(1):3058. doi: 10.1038/s41598-017-02918-3.
The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen-independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease-mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival.
非典型 C-X-C 趋化因子受体 7（CXCR7）已被证实与多种癌症（包括前列腺癌）中支持侵袭性癌症表型的发生有关。然而，该受体在癌症中过表达的机制仍知之甚少。本研究探讨了雄激素受体（AR）在调节 CXCR7 中的作用。雄激素剥夺或 AR 抑制显著增加了雄激素反应性前列腺癌细胞系中 CXCR7 的表达，同时增强了表皮生长因子受体（EGFR）介导的有丝分裂信号，通过非雄激素依赖的信号转导程序促进肿瘤细胞存活。通过多种方法，我们证明 AR 直接与 CXCR7 启动子结合，抑制转录。CRISPR （clustered regularly interspaced short palindromic repeats） 靶向 Cas9 核酸酶介导的 CXCR7 基因编辑显示，前列腺癌细胞依赖 CXCR7 进行增殖、存活和集落形成能力。通过 CRISPR-Cas9 基因编辑敲除 CXCR7 表达会导致细胞增殖停止，严重损害 EGFR 信号，并引发细胞衰老。对表达突变型 CXCR7 的 LNCaP 细胞克隆的特征分析表明，细胞内信号发生改变，球体形成能力降低。我们的研究结果表明，CXCR7 是与雄激素剥夺疗法（ADT）联合进行辅助治疗的一个潜在靶点，可用于预防雄激素非依赖性肿瘤细胞存活。
