摘要
雄激素受体(AR)在去势抵抗性前列腺癌(CRPC)的发生过程中具有关键的调控作用,其中以雄激素受体变异体7(AR-V7)为代表的组成型活性变异体水平在CRPC进展过程中不断升高,可以作为判断CRPC患者疾病进展和预后的分子标志物,是克服去势抵抗、提高患者生存质量和生存期的重要靶标。研究结果表明,AR-V7的生成与AR基因结构重排、基因扩增和AR基因转录本选择性剪接有关,且受转化生长因子-β(TGF-β)等多个信号通路分子的协同调节;AR-V7改变了AR蛋白的转运与核定位机制,并进一步影响下游靶基因的转录表达。AR-V7抗AR活性而阻断AR和雄激素驱动的分化过程,阻遏抑癌基因的表达,刺激肿瘤细胞增殖,从而促进前列腺癌进展。相关靶向研究目前主要集中在AR-V7蛋白降解、mRNA表达抑制和N端结构域靶向干预等3个方面。随着研究的深入开展,AR-V7在前列腺癌进展中的分子机制将逐步阐明,将对CRPC的预防和治疗起到更大的推动作用。
Androgen receptor(AR)plays a key regulatory role in the development of castration resistant prostate cancer(CRPC),and the level of constitutive active variants represented by androgen receptor variant 7(AR-V7)is increasing during the progress of CRPC,which can be used as a molecular marker of disease progress and prognosis of patients with CRPC.It is an important target to overcome castration resistance and improve the quality of life and survival of patients.In this paper,the function of AR-V7 and its molecular regulation mechanism in CRPC are reviewed.The research shows that the generation of AR-V7 is related to the structural rearrangement of AR gene,gene amplification and the selective splicing of AR gene transcripts,and it is affected by the coordinated regulation of multiple signal pathway molecules such as TGF-β;AR-V7 changes the transport and nuclear localization mechanism of AR protein,and further affects the transcriptional expression of downstream target genes.AR-V7 antagonizes AR activity and blocks the differentiation process driven by AR and androgen,and inhibits the expression of tumor suppressor genes to stimulate the proliferation of tumor cells,thus promoting the progress of Pca.Related targeting studies have revealed AR-V7 targets and CRPC treatment strategies.Currently,they mainly focus on AR-V7 protein degradation,mRNA expression inhibition and N-terminal domain targeting intervention.With the development of in-depth research,the molecular mechanism of AR-V7 in the progress of Pea will be gradually clarified,which will certainly play a greater role in the prevention and treatment of CRPC.
作者
屈彦纯
郭嘉宁
刘桂兰
刘冉录
Qu Yanchun;Guo Jianing;Liu Guilan;Liu Ranlu(Department of Pathology,Second Hospital of Tianjin Medical University,Tianjin 30021l,China;Urology Department of the Second Hospital of Tianjin Medical University,Tianjin 300211,China)
出处
《中华泌尿外科杂志》
CAS
CSCD
北大核心
2023年第6期476-480,共5页
Chinese Journal of Urology
关键词
前列腺肿瘤
癌
雄激素受体
去势抵抗性前列腺癌
龙雄激素受体剪接变异体7
分子靶向治疗
Prostatic neoplasms
Carcinoma
Androgen receptor
Castration resistant prostate cancer
Androgen receptor splice variant 7
NMolecular targeted therapy
作者简介
通信作者:刘冉录,Email:liuranlu1976@126.com。
