GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer
GPRC5A facilitates cell proliferation through cell cycle regulation and correlates with bone metastasis in prostate cancer
复制标题
DOI：
10.1002/ijc.32554
复制
发表时间：
2019-07-22
影响因子：
6.4
通讯作者：
Imai, Yuuki
中科院分区：
文献类型：
--
作者：
Sawada, Yuichiro;Kikugawa, Tadahiko;Imai, Yuuki
患有激素难治性和/或具有骨转移的进行性前列腺癌的患者的预后差。已经研究了改善前列腺癌患者存活率的多种治疗靶点，包括孤儿GPCR。在我们的研究中，我们使用前列腺癌细胞系注册数据集的整合基因表达分析，将G蛋白偶联受体C类5组成员A（GPRC 5A）确定为候选治疗分子。TCGA数据集的Kaplan-Meier分析显示，具有高GPRC 5A表达的患者的总生存期显著较短。具有CRISPR/Cas9介导的GPRC 5A敲除的PC 3前列腺癌细胞在体外和体内均表现出显著降低的细胞增殖。RNA-seq显示GPRC 5A KO PC 3细胞具有细胞周期相关基因的表达失调，导致细胞周期停滞在G2/M期。此外，注册的基因表达谱数据集显示，GPRC 5A在有骨转移的前列腺癌患者原发灶中的表达水平高于无骨转移的患者。事实上，GPRC 5A KO PC 3细胞未能在异种移植小鼠模型中建立骨转移。此外，我们的临床研究显示，前列腺癌患者样本中GPRC 5A表达水平与骨转移以及患者的Gleason评分（GS）显著相关。GPRC 5A和GS联合检测对骨转移的预测具有较高的特异性。总之，我们的研究结果表明，GPRC 5A可以成为进展性前列腺癌的可能治疗靶点和预后标志物分子。
The prognosis of patients with progressive prostate cancers that are hormone refractory and/or have bone metastasis is poor. Multiple therapeutic targets to improve prostate cancer patient survival have been investigated, including orphan GPCRs. In our study, we identified G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5A) as a candidate therapeutic molecule using integrative gene expression analyses of registered data sets for prostate cancer cell lines. Kaplan-Meier analysis of TCGA data sets revealed that patients who have high GPRC5A expression had significantly shorter overall survival. PC3 prostate cancer cells with CRISPR/Cas9-mediated GPRC5A knockout exhibited significantly reduced cell proliferation both in vitro and in vivo. RNA-seq revealed that GPRC5A KO PC3 cells had dysregulated expression of cell cycle-related genes, leading to cell cycle arrest at the G2/M phase. Furthermore, the registered gene expression profile data set showed that the expression level of GPRC5A in original lesions of prostate cancer patients with bone metastasis was higher than that without bone metastasis. In fact, GPRC5A KO PC3 cells failed to establish bone metastasis in xenograft mice models. In addition, our clinical study revealed that GPRC5A expression levels in prostate cancer patient samples were significantly correlated with bone metastasis as well as the patient's Gleason score (GS). Combined assessment with the immunoreactivity of GPRC5A and GS displayed higher specificity for predicting the occurrence of bone metastasis. Together, our findings indicate that GPRC5A can be a possible therapeutic target and prognostic marker molecule for progressive prostate cancer.