表现出神经内分泌 (NE) 分化的一种特定类型的前列腺癌 (PC) 被称为 NEPC。 NEPC 对雄激素剥夺治疗几乎没有反应，并且与转移性去势抵抗性 PC (CRPC) 的发展有关，后者的预后极差。我们对 NEPC 中的遗传驱动因素和激活途径的了解有限，这阻碍了精准医学方法。 L1 细胞粘附分子 (L1CAM) 已知在转移性癌症（包括 CRPC）中发挥致癌作用。然而，L1CAM 对 NEPC 进展的影响仍然难以捉摸。使用 PC 队列和患者来源的异种移植模型的公共基因表达数据库研究了 L1CAM 表达水平。在不同的 PC 细胞中进行 L1CAM 敲除以研究体外细胞功能。 CRPC细胞系CWR22Rv1的亚系是在长期暴露于阿比特龙诱导NE分化后建立的。在肿瘤球形成条件下培养雄激素受体阴性细胞系PC3以丰富癌症干性特征。在 PC 细胞上测试了几种氧化应激诱导剂，以观察 L1CAM 介导的基因表达和细胞死亡。与 CRPC 或腺癌肿瘤相比，NEPC 中的 L1CAM 表达显着高。 L1CAM 还与 NE 标志物表达相关，并与基因表达数据库中腺癌向 NEPC 的进展以及具有 NE 分化的 CRPC 细胞相关。在癌症干性富集下，L1CAM 还促进 PC3 细胞中的癌症干性和 NE 表型。 L1CAM 也被鉴定为活性氧诱导基因，通过该基因 L1CAM 可以抵消电离辐射引发的 CRPC 细胞死亡。我们的结果揭示了 L1CAM 在 PC 中 NE 表型获得中的新作用，有助于 NE 分化相关CRPC 的治疗耐药性。© 2024 Wiley periodicals LLC。

A specific type of prostate cancer (PC) that exhibits neuroendocrine (NE) differentiation is known as NEPC. NEPC has little to no response to androgen deprivation therapy and is associated with the development of metastatic castration-resistant PC (CRPC), which has an extremely poor prognosis. Our understanding of genetic drivers and activated pathways in NEPC is limited, which hinders precision medicine approaches. L1 cell adhesion molecule (L1CAM) is known to play an oncogenic role in metastatic cancers, including CRPC. However, the impact of L1CAM on NEPC progression remains elusive.L1CAM expression level was investigated using public gene expression databases of PC cohorts and patient-derived xenograft models. L1CAM knockdown was performed in different PC cells to study in vitro cell functions. A subline of CRPC cell line CWR22Rv1 was established after long-term exposure to abiraterone to induce NE differentiation. The androgen receptor-negative cell line PC3 was cultured under the tumor sphere-forming condition to enrich cancer stemness features. Several oxidative stress inducers were tested on PC cells to observe L1CAM-mediated gene expression and cell death.L1CAM expression was remarkably high in NEPC compared to CRPC or adenocarcinoma tumors. L1CAM was also correlated with NE marker expressions and associated with the adenocarcinoma-to-NEPC progression in gene expression databases and CRPC cells with NE differentiation. L1CAM also promoted cancer stemness and NE phenotypes in PC3 cells under cancer stemness enrichment. L1CAM was also identified as a reactive oxygen species-induced gene, by which L1CAM counteracted CRPC cell death triggered by ionizing radiation.Our results unveiled a new role of L1CAM in the acquisition of the NE phenotype in PC, contributing to the NE differentiation-related therapeutic resistance of CRPC.© 2024 Wiley Periodicals LLC.