Department of Urology, CHRU-Université de Brest, Brest, France.
INSERM UMR1078, Université de Bretagne Occidentale, Brest, France.
Prostate. 2019 Dec;79(16):1793-1804. doi: 10.1002/pros.23904. Epub 2019 Sep 2.
Several studies had suggested the potential role of calcium signaling in prostate cancer (PCa) prognosis and agressiveness. We aimed to investigate selected proteins contributing to calcium (Ca ) signaling, (Orai, stromal interaction molecule (STIM), and transient receptor potential (TRP) channels) and involved in cancer hallmarks, as independent predictors of systemic recurrence after radical prostatectomy (RP).
A case-control study including 112 patients with clinically localized PCa treated by RP between 2002 and 2009 and with at least 6-years' follow-up. Patients were divided into two groups according to the absence or presence of systemic recurrence. Expression levels of 10 proteins involved in Ca signaling (TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, STIM1, STIM2, Orai1, Orai2, and Orai3), were assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from paraffin-embedded PCa specimens. The level of expression of the various transcripts in PCa was assessed using quantitative polymerase chain reaction (qPCR) analysis. RNA samples for qPCR were obtained from fresh frozen tissue samples of PCa after laser capture microdissection on RP specimens. Relative gene expression was analyzed using the method.
Multivariate analysis showed that increased expression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 was significantly associated with a lower risk of systemic recurrence after RP, independently of the prostate-specific antigen (PSA) level, percentage of positive biopsies, and surgical margin (SM) status (P = .007, P = .01, P < .001, P = .0065, P = .007, and P = .01, respectively). For TRPC4, TRPV5, and TRPV6, this association was also independent of Gleason score and pT stage. Moreover, overexpression of TRPV6 and Orai2 was significantly associated with longer time to recurrence after RP (P = .048 and .023, respectively). Overexpression of TRPC4, TRPV5, TRPV6, and Orai2 transcripts was observed in group R- (3.71-, 5.7-, 1.14-, and 2.65-fold increase, respectively).
This is the first study to suggest the independent prognostic value of certain proteins involved in Ca influx in systemic recurrence after RP: overexpression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 is associated with a lower risk of systemic recurrence. TRPC4, TRPV5, and TRPV6 appear to be particularly interesting, as they are independent of the five commonly used predictive factors, that is, PSA, percentage of positive biopsies, SM status, Gleason score, and pT stage.
几项研究表明，钙信号在前列腺癌（PCa）的预后和侵袭性中可能起作用。我们旨在研究参与钙（Ca）信号的选定蛋白（Orai、基质相互作用分子（STIM）和瞬时受体电位（TRP）通道）和涉及癌症标志的蛋白，作为根治性前列腺切除术（RP）后全身复发的独立预测因子。
这是一项病例对照研究，纳入了 112 例 2002 年至 2009 年间接受 RP 治疗的临床局限性 PCa 患者，且至少随访 6 年。根据是否存在全身复发，将患者分为两组。使用组织微阵列（TMA），通过免疫组织化学方法评估 10 种参与 Ca 信号的蛋白（TRPC1、TRPC4、TRPV5、TRPV6、TRPM8、STIM1、STIM2、Orai1、Orai2 和 Orai3）的表达水平，TMA 由石蜡包埋的 PCa 标本构建。使用定量聚合酶链反应（qPCR）分析评估 PCa 中各种转录本的表达水平。qPCR 分析的 RNA 样本来自 RP 标本的激光捕获显微解剖后的新鲜冷冻组织样本。使用 方法分析相对基因表达。
多变量分析显示，TRPC1、TRPC4、TRPV5、TRPV6、TRPM8 和 Orai2 的表达增加与 RP 后全身复发风险降低显著相关，独立于前列腺特异性抗原（PSA）水平、阳性活检百分比和手术切缘（SM）状态（P =.007、P =.01、P <.001、P =.0065、P =.007 和 P =.01，分别）。对于 TRPC4、TRPV5 和 TRPV6，这种关联也独立于 Gleason 评分和 pT 分期。此外，TRPV6 和 Orai2 的过表达与 RP 后复发时间延长显著相关（P =.048 和.023）。在组 R-中观察到 TRPC4、TRPV5、TRPV6 和 Orai2 转录物的过表达（分别为 3.71、5.7、1.14 和 2.65 倍）。
这是第一项表明参与钙内流的某些蛋白在 RP 后全身复发中的独立预后价值的研究：TRPC1、TRPC4、TRPV5、TRPV6、TRPM8 和 Orai2 的过表达与全身复发风险降低相关。TRPC4、TRPV5 和 TRPV6 似乎特别有趣，因为它们独立于常用的五种预测因子，即 PSA、阳性活检百分比、SM 状态、Gleason 评分和 pT 分期。
