外泌体MALAT1通过激活基质细胞IL6-RANKL信号通路促进前列腺癌骨转移的分子机制研究

Bone metastasis is the key clinical event of prostate cancer (PCa) progression. However, the molecular mechanism of exosomal long non-coding RNA (lncRNA) in bone metastasis of PCa remains elusive. Our previous RNA-seq data demonstrated that exosomal lncRNA MALAT1 was significantly correlated with PCa bone metastasis. Further study showed that exosomal MALAT1 could enhance the capability of the migration and invasion in PCa cell lines. Furthermore, our preliminary research on molecular mechanism showed that exosomal MALAT1 could significantly enhance the expression of IL6 in bone stromal cells. Based on previous study, we will firstly study the biological function of exosomal MALAT1 in promoting the bone metastasis of PCa in vitro and in vivo. Subsequently, we will explore the molecular mechanism of exosomal MALAT1 in enhancing the expression of IL6 in bone stromal cells. Besides, we will further investigate the role of exosomal MALAT1 in activation of IL6-RANKL signaling pathway, confirming the hypothesis that exosomal MALAT1 triggers skeletal metastatic niche by engaging tumor-stromal cell interactions and then promotes PCa bone metastasis. The study will finally elucidate the key molecular events of exosomal MALAT1 in regulating bone metastasis of PCa, which might provide novel targets and its theoretical foundation for clinical early warning and intervention of PCa bone metastasis.

骨转移是前列腺癌(PCa)进展最关键的临床事件。然而，外泌体长链非编码RNA(lncRNA)在PCa骨转移中的分子机制不明。我们前期运用RNA-seq找到了与PCa骨转移显著相关的外泌体lncRNA MALAT1，且外泌体MALAT1能够显著提高PCa细胞的迁移和侵袭能力。初步机制研究表明，外泌体MALAT1能够显著提高骨基质细胞IL6的表达。本项目在前期研究基础上，首先，运用体外和体内实验研究外泌体MALAT1在促进PCa骨转移中的生物学功能；进一步探索外泌体MALAT1促进骨基质细胞IL6表达的分子机制；探明外泌体MALAT1对于基质细胞IL6-RANKL的激活作用，论证外泌体MALAT1通过“驯化”基质细胞促进PCa细胞形成骨转移前灶进而促进PCa骨转移的假说。最终，阐明外泌体MALAT1在促进PCa骨转移这一关键分子事件中的分子机制，为PCa骨转移的临床预警及干预提供新的靶点。

骨转移是前列腺癌（PCa）进展最关键的临床事件。然而，外泌体长链非编码RNA（lncRNA）在PCa骨转移中的分子机制不明。我们前期运用RNA-seq找到了PCa骨转移显著相关的外泌体lncRNA MALAT1，且外泌体MALAT1能够显著提高PCa细胞的迁移和侵袭能力。初步机制研究表明，外泌体MALAT1能够显著提高骨基质细胞IL6的表达。本项目在前期研究基础上，开展如下研究：运用体外和体内实验研究外泌体MALAT1在促进PCa骨转移中的生物学功能；探索外泌体MALAT1促进骨基质细胞IL6表达的分子机制；探明外泌体MALAT1对于基质细胞IL6-RANKL的激活作用。.通过本项目的研究，我们首先运用体外和体内实验论证了外泌体MALAT1通过肿瘤-基质细胞相互作用在促进PCa骨转移中的生物学功能。此后，我们阐述了外泌体MALAT1通过稳定细胞质中IL6的mRNA水平促进IL6表达的分子机制，从而进一步探明外泌体MALAT1对于基质细胞IL6-RANKL的激活作用，论证了外泌体MALAT1通过“驯化”基质细胞促进PCa细胞形成骨转移前灶进而促进PCa骨转移的假说。此外，我们还阐明了外泌体MALAT1通过结合并稳定糖代谢关键酶——ALDOA，PGK1蛋白的表达，实现PCa糖代谢重编程，进一步促进肿瘤进展，这一发现进一步丰富了细胞质中MALAT1通过糖代谢重编程促进PCa进展的分子机制，为晚期PCa的治疗提供了又一新的靶点。.在本项目资助下，我们完成了既定目标，获得了多项具有自主知识产权的成果，发表SCI论文7篇，获得国家发明专利1项，申请发明专利2项。协助培养博士研究生2名，硕士研究生2名。