神经内分泌前列腺癌（NEPC）是去势抵抗前列腺癌(CRPC)的高度恶性亚型，其发生机制尚不明确。我们已报导：核受体TLX可通过抑制雄激素受体AR促进前列腺癌雄激素非依赖生长。新近发现：TLX可促进NE分化标记物的表达和OCT4转录，并与AR呈负相关；TLX还可促进前列腺癌转移及雄激素合成酶表达。基于此，我们推测TLX与AR形成负调节环路，通过调控OCT4、TGF-β及雄激素合成途径，促进NEPC的分化和恶性生长。本项目拟通过建立NEPC细胞和动物模型，检测TLX在NEPC临床样本和NE分化过程中的动态表达，研究TLX促进NEPC发生的功能；同时，通过深入探讨AR对TLX的转录抑制，以及TLX对OCT4、TGF-β通路和雄激素合成途径关键酶的调控，鉴定出TLX促进NEPC发生和恶性进展的作用机制。本研究成果将首次阐明TLX促进NEPC发生和恶性进展的作用机制，为晚期难治性前列癌提供新靶标。

Neuroendocrine prostate cancer (NEPC) is a more malignant subtype of castrate-resistant prostate cancer (CRPC) with worse prognosis, and its molecular mechanism is poorly understood. We have systematically reported the important functional role of nuclear receptor TLX in the tumorigenesis and malignant progression of prostate cancer. Recent studies showed TLX expression was positively correlated with NEPC markers but show negatively correlation with AR signaling pathway. NEPC markers were significantly increased in TLX overexpressed cells. Moreover, TLX can promote the in vivo metastasis growth of prostate cancer accompanied with transcription activation of TGF-β signaling pathway genes and the increased expression of androgen syntheses genes induced by TLX. Based on these interesting results, we hypothesis that TLX plays an important role in transformation and malignant growth of NEPC development. This project intends to: 1) validate the expression correlation between TLX signaling and the progress of NEPC; 2) further investigate the functional role of TLX in NEPC cell differentiation, metastasis, intratumoral androgen biosynthesis and malignant growth of NEPC; 3) elucidating the underlying mechanism of TLX pathway in NEPC progression; 4) preliminary investigation of the therapeutic significance of TLX as a target of NEPC treatment. The results of this study will, for the first time, elucidate the function and mechanism of nuclear receptor TLX in promoting the progression of NEPC and provide scientific basis for establishment of therapeutic target of TLX for advanced prostate cancer.