RGS2 is prognostic for development of castration resistance and cancer-specific survival in castration-resistant prostate cancer
RGS2 is prognostic for development of castration resistance and cancer-specific survival in castration-resistant prostate cancer
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DOI：
10.1002/pros.23994
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发表时间：
2020-05-25
期刊：
影响因子：
2.8
通讯作者：
Damber, Jan-Erik
中科院分区：
文献类型：
--
作者：
Linder, Anna;Larsson, Karin;Damber, Jan-Erik
G蛋白信号调节因子2（Regulator of G-protein signaling 2，RGS2）是一种多方面的蛋白质，在未经治疗的前列腺癌（PC）中具有预后价值。它以前与去势抵抗的发展有关。然而，RGS2在去势抵抗性前列腺癌（CRPC）临床标本中的表达及其临床相关性尚未探讨。在本研究中，RGS2评估CRPC和去势resistance.Methods的发展，在本研究中，RGS2的表达进行了评价与免疫组织化学在患者材料的首次治疗和去势抵抗原发性肿瘤，也在匹配标本前和3个月后的雄激素剥夺治疗（ADT）。采用考克斯回归和Kaplan-Meier曲线分析RGS2表达的临床意义。在CRPC的原位异种移植小鼠模型中，通过实验评估RGS2表达与去势抵抗性生长的相关性。在体外，进行LNCaP的激素耗竭和LNCaP、22 Rv1和VCaP的Enzalutamide处理，以评价RGS2与雄激素受体（AR）之间的相关性。使用稳定的RGS2敲低来评估RGS2与在酶还原条件下PC细胞生长相关的影响。结果RGS2在CRPC中的表达增加，在ADT作用下RGS2的表达增加。此外，高RGS2水平是CRPC患者癌症特异性生存期较差的预后指标，并显著降低了开始ADT后的无失败生存期（FFS）。此外，RGS2在FFS方面的预后价值优于前列腺特异性抗原（PSA）。本研究进一步表明，RGS2表达反映了AR活性。此外，低RGS2表达的细胞显示生长受阻的条件下，减少的条件下，在与高RGS2 expression.Conclusions高水平的RGS2相关的不良预后与去势抵抗PC的侵略性形式。结果表明，高水平的RGS2与去势抵抗性PC生长相关的不良预后相关。单独使用RGS2或与PSA联合使用，有可能在ADT期间的早期阶段识别需要额外治疗的患者。
Background Regulator of G-protein signaling 2 (RGS2) is a multifaceted protein with a prognostic value in hormone-naive prostate cancer (PC). It has previously been associated with the development of castration resistance. However, RGS2 expression in clinical specimens of castration-resistant prostate cancer (CRPC) and its clinical relevance has not been explored. In the present study, RGS2 was assessed in CRPC and in relation to the development of castration resistance.Methods In the present study, RGS2 expression was evaluated with immunohistochemistry in patient materials of hormone-naive and castration-resistant primary tumors, also in matched specimens before and after 3 months of androgen deprivation therapy (ADT). Cox regression and Kaplan-Meier curves were used to evaluate the clinical significance of RGS2 expression. RGS2 expression in association to castration-resistant growth was assessed experimentally in an orthotopic xenograft mouse model of CRPC. In vitro, hormone depletion of LNCaP and enzalutamide treatment of LNCaP, 22Rv1, and VCaP was performed to evaluate the association between RGS2 and the androgen receptor (AR). Stable RGS2 knockdown was used to evaluate the impact of RGS2 in association to PC cell growth under hormone-reduced conditions. Gene and protein expression were evaluated with quantitative polymerase chain reaction and Western blot analysis, respectively.Results RGS2 expression is increased in CRPC and enriched under ADT. Furthermore, a high RGS2 level is prognostic for poor cancer-specific survival for CRPC patients and significantly reduced failure-free survival (FFS) after an initiated ADT. Additionally, the prognostic value of RGS2 outperforms prostate-specific antigen (PSA) in terms of FFS. The present study furthermore suggests that RGS2 expression is reflective of AR activity. Moreover, low RGS2-expressing cells display hampered growth under hormone-reduced conditions, in line with the poor prognosis associated with high RGS2 expression.Conclusions High levels of RGS2 are associated with aggressive forms of castration-resistant PC. The results demonstrate that a high level of RGS2 is associated with poor prognosis in association with castration-resistant PC growth. RGS2 alone, or in association with PSA, has the potential to identify patients that require additional treatment at an early stage during ADT.