Sreekumar Amritha, Saini Sharanjot
Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA.
Noncoding RNA. 2022 Mar 30;8(2):25. doi: 10.3390/ncrna8020025.
Therapy-induced neuroendocrine prostate cancer (t-NEPC/NEPC) is an aggressive variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC) under the selective pressure of androgen receptor (AR)-targeted therapies. This variant is extremely aggressive, metastasizes to visceral organs, tissues, and bones despite low serum PSA, and is associated with poor survival rates. It arises via a reversible trans-differentiation process, referred to as 'neuroendocrine differentiation' (NED), wherein PCa cells undergo a lineage switch and exhibit neuroendocrine features, characterized by the expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA), and synaptophysin (SYP). The molecular and cellular mechanisms underlying NED in PCa are complex and not clearly understood, which contributes to a lack of effective molecular biomarkers for diagnosis and therapy of this variant. NEPC is thought to derive from prostate adenocarcinomas by clonal evolution. A characteristic set of genetic alterations, such as dual loss of retinoblastoma () and tumor protein () tumor suppressor genes and amplifications of Aurora kinase A (), , and , has been reported to drive NEPC. Recent evidence suggests that microRNAs (miRNAs) are important epigenetic players in driving NED in advanced PCa. In this review, we highlight the role of miRNAs in NEPC. These studies emphasize the diverse role that miRNAs play as oncogenes and tumor suppressors in driving NEPC. These studies have unveiled the important role of cellular processes such as the EMT and cancer stemness in determining NED in PCa. Furthermore, miRNAs are involved in intercellular communication between tumor cells and stromal cells via extracellular vesicles/exosomes that contribute to lineage switching. Recent studies support the promising potential of miRNAs as novel diagnostic biomarkers and therapeutic targets for NEPC.
治疗诱导的神经内分泌前列腺癌（t-NEPC/NEPC）是前列腺癌（PCa）的一种侵袭性变体，常在雄激素受体（AR）靶向治疗的选择性压力下，于去势抵抗性前列腺癌（CRPC）中频繁出现。这种变体极具侵袭性，尽管血清前列腺特异抗原（PSA）水平较低，但仍会转移至内脏器官、组织和骨骼，且与低生存率相关。它通过一种可逆的转分化过程产生，即“神经内分泌分化”（NED），在此过程中，PCa细胞发生谱系转换并表现出神经内分泌特征，其特征为神经元标志物如烯醇化酶2（ENO2）、嗜铬粒蛋白A（CHGA）和突触素（SYP）的表达。PCa中NED的分子和细胞机制复杂且尚未完全明确，这导致缺乏针对该变体诊断和治疗的有效分子生物标志物。NEPC被认为是通过克隆进化从前列腺腺癌衍生而来。据报道，一组特征性的基因改变，如视网膜母细胞瘤（RB）和肿瘤蛋白p53（TP53）肿瘤抑制基因的双重缺失以及极光激酶A（AURKA）、MYC和FOXA1的扩增，驱动了NEPC的发生。最近的证据表明，微小RNA（miRNA）是晚期PCa中驱动NED的重要表观遗传因子。在本综述中，我们强调了miRNA在NEPC中的作用。这些研究强调了miRNA作为癌基因和肿瘤抑制因子在驱动NEPC中所起的多种作用。这些研究揭示了上皮-间质转化（EMT）和癌症干性等细胞过程在决定PCa中的NED方面的重要作用。此外，miRNA通过细胞外囊泡/外泌体参与肿瘤细胞与基质细胞之间的细胞间通讯，这有助于谱系转换。最近的研究支持了miRNA作为NEPC新型诊断生物标志物和治疗靶点的潜在前景。
