Lee Ahn R, Che Nicole, Lovnicki Jessica M, Dong Xuesen
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Front Oncol. 2018 Apr 3;8:93. doi: 10.3389/fonc.2018.00093. eCollection 2018.
While the use of next-generation androgen receptor pathway inhibition (ARPI) therapy has significantly increased the survival of patients with metastatic prostate adenocarcinoma (AdPC), several groups have reported a treatment-resistant mechanism, whereby cancer cells can become androgen receptor (AR) indifferent and gain a neuroendocrine (NE)-like phenotype. This subtype of castration-resistant prostate cancer has been termed "treatment-induced castration-resistant neuroendocrine prostate cancer" (CRPC-NE). Recent reports indicate that the overall genomic landscapes of castration-resistant tumors with AdPC phenotypes and CRPC-NE are not significantly altered. However, CRPC-NE tumors have been found to contain a NE-specific pattern throughout their epigenome and splicing transcriptome, which are significantly modified. The molecular mechanisms by which CRPC-NE develops remain unclear, but several factors have been implicated in the progression of the disease. Recently, Ser/Arg repetitive matrix 4 (SRRM4), a neuronal-specific RNA splicing factor that is upregulated in CRPC-NE tumors, has been shown to establish a CRPC-NE-unique splicing transcriptome, to induce a NE-like morphology in AdPC cells, and, most importantly, to transform AdPC cells into CRPC-NE xenografts under ARPI. Moreover, the SRRM4-targeted splicing genes are highly enriched in various neuronal processes, suggesting their roles in facilitating a CRPC-NE program. This article will address the importance of SRRM4-mediated alternative RNA splicing in reprogramming translated proteins to facilitate NE differentiation, survival, and proliferation of cells to establish CRPC-NE tumors. In addition, we will discuss the potential roles of SRRM4 in conjunction with other known pathways and factors important for CRPC-NE development, such as the AR pathway, and genes, the FOXA family of proteins, and environmental factors. This study aims to explore the multifaceted functions of SRRM4 and SRRM4-mediated splicing in driving a CRPC-NE program as a coping mechanism for therapy resistance, as well as define future SRRM4-targeted therapeutic approaches for treating CRPC-NE or mitigating its development.
虽然使用下一代雄激素受体通路抑制（ARPI）疗法显著提高了转移性前列腺腺癌（AdPC）患者的生存率，但多个研究小组报告了一种治疗抵抗机制，即癌细胞可变得对雄激素受体（AR）不敏感，并获得神经内分泌（NE）样表型。这种去势抵抗性前列腺癌亚型被称为“治疗诱导的去势抵抗性神经内分泌前列腺癌”（CRPC-NE）。最近的报告表明，具有AdPC表型的去势抵抗性肿瘤和CRPC-NE的总体基因组格局没有明显改变。然而，已发现CRPC-NE肿瘤在其整个表观基因组和剪接转录组中包含一种NE特异性模式，这些均发生了显著改变。CRPC-NE发生发展的分子机制仍不清楚，但几个因素与该疾病的进展有关。最近，丝氨酸/精氨酸重复基质4（SRRM4），一种在CRPC-NE肿瘤中上调的神经元特异性RNA剪接因子，已被证明可建立CRPC-NE独特的剪接转录组，在AdPC细胞中诱导NE样形态，并且最重要的是，在ARPI作用下将AdPC细胞转化为CRPC-NE异种移植瘤。此外，SRRM4靶向的剪接基因在各种神经元过程中高度富集，表明它们在促进CRPC-NE程序中的作用。本文将阐述SRRM4介导的可变RNA剪接在重新编程翻译后的蛋白质以促进NE细胞分化、存活和增殖以建立CRPC-NE肿瘤中的重要性。此外，我们将讨论SRRM4与其他已知的对CRPC-NE发生发展重要的途径和因素（如AR途径、基因、FOXA蛋白家族和环境因素）协同发挥的潜在作用。本研究旨在探索SRRM4和SRRM4介导的剪接在驱动CRPC-NE程序作为治疗抵抗应对机制方面的多方面功能，并确定未来针对SRRM4的治疗方法，用于治疗CRPC-NE或减缓其发展。
