潜在调控信号分子的上调与前列腺癌转移中的雄激素受体剪接变异体 AR-V7 和 AR-V567es 相关。

Upregulation of potential regulatory signaling molecules correlate with androgen receptor splice variants AR-V7 and AR-V567es in prostate cancer metastasis.

机构信息

Department of Medical Biology and Genetics, Faculty of Medicine, Gazi University, Besevler, 06510, Ankara, Turkey.

Department of Urology, Faculty of Medicine, Hacettepe University, Sıhhiye, 06100, Ankara, Turkey.

出版信息

Gene. 2021 Mar 10;772:145377. doi: 10.1016/j.gene.2020.145377. Epub 2021 Jan 5.

DOI:10.1016/j.gene.2020.145377

PMID:33359129

Abstract

AIM

Androgen receptor splice variants (AR-Vs) produced by alternative splicing of the AR play an important role in the treatment resistance and progression of prostate cancer (PCa). In this study, two most common AR variants and how they associate with the inflammatory response (NF-Kβ) and regulatory transcriptional activity (HSP-27) genes were investigated in patients with PCa and metastatic PCa (Met-PCa).

METHODS

Our study was carried out with the whole blood obtained from 25 healthy control subjects, 25 PCa patients and 39 Met-PCa patients. We examined the expression levels of AR, AR-V7 and AR-V567es genes via Real-time PCR and those of HSP-27 and NF-Kβ via ELISA method.

RESULTS

AR, AR-V7 and AR-V567es expressions were observed in 84.61%, 64.1%, 23.07% of Met-PCa patients respectively. The expression levels of full-length AR and variants (AR-V7 and AR-V567es) were associated with the prostate cancer stage. In the Met-PCa, the expression levels of AR, AR-V7 and AR-V567es were associated with the Gleason Scores but not with the PSA levels. AR-V7 expression levels in stage T4 patients significantly increased. NF-Kβ and HSP-27 protein levels were significantly higher in Met-PCa patients.

DISCUSSION

Our findings highlight the targeting of the proteostasis and inflammation pathways through inhibiting HSP-27 and NF-Kβ. This might be a valuable strategy to overcome anti-androgen resistance and improve drug therapy in Met-PCa patients whose gene expression levels of AR-V7 and AR-V567es variants are high.

摘要

目的

雄激素受体剪接变异体（AR-Vs）通过雄激素受体的选择性剪接产生，在前列腺癌（PCa）的治疗抵抗和进展中发挥重要作用。在这项研究中，研究人员研究了两种最常见的 AR 变体，以及它们如何与炎症反应（NF-Kβ）和调节转录活性（HSP-27）基因相关，研究对象为 PCa 患者和转移性 PCa（Met-PCa）患者。

方法

本研究采用 25 名健康对照者、25 名 PCa 患者和 39 名 Met-PCa 患者的全血进行。通过实时 PCR 检测 AR、AR-V7 和 AR-V567es 基因的表达水平，通过 ELISA 法检测 HSP-27 和 NF-Kβ 的表达水平。

结果

Met-PCa 患者中分别观察到 84.61%、64.1%和 23.07%的患者存在 AR、AR-V7 和 AR-V567es 的表达。全长 AR 和变体（AR-V7 和 AR-V567es）的表达水平与前列腺癌分期相关。在 Met-PCa 中，AR、AR-V7 和 AR-V567es 的表达水平与 Gleason 评分相关，但与 PSA 水平无关。T4 期患者的 AR-V7 表达水平显著升高。Met-PCa 患者的 NF-Kβ 和 HSP-27 蛋白水平显著升高。