Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Cancer Lett. 2024 Aug 10;597:217068. doi: 10.1016/j.canlet.2024.217068. Epub 2024 Jun 18.
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
随着抗雄激素治疗（如阿比特龙和恩扎鲁胺）的广泛应用，神经内分泌前列腺癌（NEPC）的发病率正在增加。NEPC 是一种致命形式的前列腺癌（PCa），在诊断后中位总生存期不到一年。除了 PCa 中常见的骨转移外，NEPC 还表现出内脏转移的特征，特别是肝转移，这在临床上是预后不良的标志。已经确定了驱动 PCa 神经内分泌可塑性的关键因素，但肝转移背后的潜在机制尚不清楚。在这项研究中，我们鉴定出 PROX1 是 PCa 神经内分泌可塑性的驱动因素，负责促进肝转移。从机制上讲，抗雄激素治疗缓解了 PROX1 的转录抑制。随后，升高的 PROX1 水平既促进了神经内分泌可塑性，又促进了肝脏特异性转录重编程，从而促进了肝转移。此外，由 PROX1 诱导的 PCa 肝转移依赖于重编程的脂质代谢，这种破坏有效地减少了肝转移的形成。
