lncRNA-PMAT1募集hnRNPA1调控β-catenin/c-Myc正反馈环路促进前列腺癌淋巴转移的机制研究

The lymphatic metastasis is the main reason for poor prognosis in prostate cancer. Our previous study found that lncRNA-PMAT1 is highly expressed in metastatic lymph nodes of prostate cancer, but the specific mechanism of lncRNA-PMAT1 regulating lymphatic metastasis is not clear. Recently, our data suggest that lncRNA-PMAT1 is involved in the activation of Wnt / β-catenin signaling pathway by interacting with hnRNPA1. Therefore, we propose a new mechanism of lncRNA-PMAT1 in regulating lymphatic metastasis. LncRNA-PMAT1 activates β-catenin expression by recruiting hnRNPA1 to the β-catenin promoter, which leads to regulate the positive feedback regulation of Wnt/β-catenin/c-Myc signaling pathway and promote lymphatic metastasis of prostate cancer. Furthermore, we will investigate that lncRNA-PMAT1 regulates lymphatic metastasis by recruiting hnRNPA1 by in vitro and in vivo experiments and chromatin immunoprecipitation. The success of this study may reveal new mechanisms for lymphatic metastasis of prostate cancer in the future.

前列腺癌发生淋巴转移是患者预后差的主要原因。我们前期研究证实，lncRNA-PMAT1在前列腺癌转移淋巴结中高表达，并促进前列腺癌转移，但具体调控机制尚不清楚。近期预实验结果表明，lncRNA-PMAT1与hnRNPA1结合，激活Wnt/β-catenin信号通路。据此，我们提出lncRNA-PMAT1调控前列腺癌转移的科研假设：lncRNA-PMAT1通过募集hnRNPA1与β-catenin启动子形成三聚体，促进β-catenin表达上调，提高下游转录因子c-Myc表达，参与Wnt/β-catenin/c-Myc信号通路正反馈调节，诱导前列腺癌淋巴转移。本课题拟进一步通过动物实验和染色质免疫共沉淀等技术，阐明lncRNA-PMAT1在介导β-catenin/c-Myc正反馈环路促进前列腺癌淋巴转移中的关键作用及调控机制，为确立lncRNA-PMAT1作为前列腺癌治疗新靶点提供科学依据。

前列腺癌是我国泌尿生殖系统最常见的恶性肿瘤之一，严重影响男性健康。既往研究表明前列腺癌发生淋巴转移是患者预后差的主要原因，发生淋巴转移的患者术后生化复发率和临床复发率明显升高。因此，阐明前列腺癌淋巴转移的关键分子机制，将为抑制前列腺癌淋巴转移提供理论基础，为前列腺癌诊断和靶向治疗提供新的思路。为了探究前列腺癌淋巴转移的具体分子机制，我们通过高通量测序筛选鉴定出在淋巴转移性前列腺癌中高表达的lncRNA-PMAT1，并扩大临床样本证实lncRNA-PMAT1与前列腺癌患者的淋巴转移和不良预后成正相关。通过体外功能实验，我们证实lncRNA-PMAT1显著促进前列腺癌的侵袭迁移及诱导淋巴管内皮细胞成管能力；体内动物实验证实lncRNA-PMAT1通过诱导淋巴管新生而促进前列腺癌淋巴转移。在分子机制中，我们发现lncRNA-PMAT1与hnRNPA1结合，并与β-catenin启动子区形成三聚体结构而促进β-catenin启动子区H3K4me3组蛋白修饰而促进β-catenin的转录激活，从而激活Wnt/β-catenin/c-Myc信号通路。并且转录因子c-Myc反过来可以促进lncRNA-PMAT1的转录，从而形成正反馈环路而持续性激活Wnt/β-catenin/c-Myc信号通路，最终促进前列腺癌的淋巴转移。本项目详细阐述了lncRNA-PMAT1促进前列腺癌淋巴转移的具体分子机制，为确立lncRNA-PMAT1作为前列腺癌淋巴转移早期诊断的分子标志物及治疗新靶点提供科学依据。在该项目的支持下，共发表SCI文章10篇，其中IF>10分8篇；获得国家知识产权局授权实用新型专利2项；顺利完成2名博士研究生和1名硕士研究生的培养工作。