癌症研究
生物
前列腺癌
转分化
基因沉默
下调和上调
恩扎鲁胺
SOX2
神经内分泌分化
细胞生物学
细胞
转录因子
癌症
雄激素受体
遗传学
基因
作者
Jing Wang,Jingjing Li,Yin Liu,Tianjie Pu,Jing Wei,Varsha Karthikeyan,Tao Lin,Allen C. Gao,Bainan Wu
出处
期刊:Oncogene
[Springer Nature]
日期:2022-08-19
卷期号:41 (37): 4307-4317
被引量:5
标识
DOI:10.1038/s41388-022-02437-0
摘要
Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.
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