State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Science/Xiangya Hospital, Central South University, Changsha, China.
Oncogene. 2018 Feb 15;37(7):935-943. doi: 10.1038/onc.2017.399. Epub 2017 Oct 23.
Neuropilin-1 (NRP1) is a non-kinase receptor recently implicated in tumor progression. Here we revealed that over-expression of NRP1 correlates with poor prognosis in esophageal squamous cell carcinoma (ESCC). NRP1-knockdown suppressed ESCC cell proliferation and xenograft tumor growth. Reduced NRP1 expression downregulated P65 mRNA and protein expression, and ectopic expression of P65-restored cell proliferation in NRP1-silenced cells. NRP1 regulates P65 transcription by activating cAMP responsive element binding protein (CREB). NRP1 interacted with and activated epidermal growth factor receptor (EGFR), and b1/b2 domain of NRP1 is responsible for the activation of EGFR. We also found that EGFR regulated CREB transcriptional activity via AKT. These data suggest that NRP1 is an upstream regulator in the P65-dependent proliferation signaling pathway and a candidate therapeutic target for ESCC.
神经纤毛蛋白-1（NRP1）是一种非激酶受体，最近被发现与肿瘤进展有关。在这里，我们揭示了 NRP1 的过表达与食管鳞状细胞癌（ESCC）的预后不良相关。NRP1 敲低抑制了 ESCC 细胞的增殖和异种移植肿瘤的生长。NRP1 表达的降低下调了 P65 mRNA 和蛋白的表达，而 P65 的异位表达则恢复了 NRP1 沉默细胞的增殖。NRP1 通过激活 cAMP 反应元件结合蛋白（CREB）来调节 P65 的转录。NRP1 与表皮生长因子受体（EGFR）相互作用并激活 EGFR，而 NRP1 的 b1/b2 结构域负责激活 EGFR。我们还发现 EGFR 通过 AKT 调节 CREB 的转录活性。这些数据表明，NRP1 是 P65 依赖性增殖信号通路中的上游调节剂，是 ESCC 的候选治疗靶点。
