Department of Urology, Ehime University Graduate School of Medicine, Toon, Japan.
Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Japan.
Int J Cancer. 2020 Mar 1;146(5):1369-1382. doi: 10.1002/ijc.32554. Epub 2019 Jul 22.
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.
对于激素难治性和/或发生骨转移的进行性前列腺癌患者，其预后较差。已经研究了多种治疗靶点以改善前列腺癌患者的生存，包括孤儿 GPCR。在我们的研究中，我们使用前列腺癌细胞系的注册数据集的综合基因表达分析，确定了 G 蛋白偶联受体 C 类组 5 成员 A（GPRC5A）作为候选治疗分子。TCGA 数据集的 Kaplan-Meier 分析显示，GPRC5A 高表达的患者总生存期明显缩短。CRISPR/Cas9 介导的 GPRC5A 敲除的 PC3 前列腺癌细胞在体外和体内均表现出明显降低的细胞增殖。RNA-seq 显示，GPRC5A KO PC3 细胞中与细胞周期相关的基因表达失调，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，具有骨转移的前列腺癌患者原始病变中 GPRC5A 的表达水平高于无骨转移的患者。事实上，GPRC5A KO PC3 细胞未能在异种移植小鼠模型中建立骨转移。此外，我们的临床研究表明，前列腺癌患者样本中 GPRC5A 的表达水平与骨转移以及患者的 Gleason 评分（GS）显著相关。GPRC5A 的免疫反应性与 GS 的联合评估显示出更高的特异性，可预测骨转移的发生。总之，我们的研究结果表明，GPRC5A 可能是进行性前列腺癌的一种潜在治疗靶点和预后标志物分子。
