外泌体通过miR-141-3p调控前列腺癌骨转移微环境的作用机制及干预研究

Studies have shown that exosome can regulated the microenvironment to promote tumor metastasis through the transfer of miRNA, but the molecular mechanism in prostate cancer is still unclear. Previous study we have found that, 1) Exosomal miR-141-3p is upregulated in the serum of prostate cancer (PCa) patients, which is related to bone metastasis. 2) Exosomal miR-141-3p from PCa cells participated in intercellular communication and promoted osteogensis metastasis of PCa. 3) DLC1, FOXA1, TCF4 and PTPN2 were the target gene of miR-141-3p and miR-141-3p negatively regulates their expression. Based on this, we speculate that the exosome derived from PCa cells could mediate miR-141-3p transport to the potential transfer sites and promote tumor metastasis. The process may be associated with related signaling pathways. To identify this hypothesis, employing cell and molecule, mice model, human sample, this study intends to clarify the role and molecular mechanism of exosomal miR-141-3p from PCa in regulating the microenvironment of bone metastasis, and explore the effectiveness of miR-141-3p/ pathway/osteogenesis inhibitors on the treatment of bone metastasis, in order to lay the foundation for basic and clinical research of bone metastatic PCa.

研究表明外泌体可通过转运miRNA，调节肿瘤微环境促进肿瘤转移，但在前列腺癌的发生发展中具体机制尚不清楚。本课题组前期研究发现：①前列腺癌患者血清exosomal miR-141-3p表达升高且与转移相关；②初步证实exosomal miR-141-3p参与细胞间通讯并具有促进前列腺癌成骨性骨转移的作用；③预实验结果显示抑癌基因DLC1,FOXA1,TCF4和PTPN2为miR-141-3p作用靶基因。据此我们推测前列腺癌细胞外泌体介导miR-141-3p 转运改造转移微环境，该过程可能系exosomal miR-141-3p 与相关通路的共同调控所致。本课题拟从三个层面研究exosomal miR-141-3p调控前列腺癌骨转移微环境的作用及分子机制，并探讨miR-141-3p/通路/成骨抑制剂对前列腺癌骨转移的治疗有效性，以期为前列腺癌骨转移的基础和临床研究奠定基础。

在前列腺癌(PCa)患者中，x线结果显示骨病变多为成骨性的;然而，病理性骨折却经常发生在前列腺癌患者中，在组织病理学评估中，所有转移病灶都观察到了骨吸收。前列腺癌患者中平衡成骨细胞和破骨细胞活性的机制尚不清楚。我们意外地发现PCa外泌体是调节骨稳态的关键介质，导致骨缺损从而促进骨肿瘤生长。我们评估了来自成骨性、破骨性和混合性的PCa细胞系外泌体对成骨细胞和破骨细胞的影响，发现所有三种类型的PCa外泌体在体外促进破骨细胞的发生，并诱导体内的骨溶解。在机制上，PCa外泌体传递的microRNAs (miRNAs)在骨稳态中发挥了关键的作用。在递送的miRNA中，miR-92a-1-5p含量最高，通过直接靶向COL1A1下调I型胶原表达，从而促进破骨细胞分化，抑制成骨细胞形成。此外，PCa外泌体也显著降低了I型胶原蛋白在体内的表达。我们的发现为肿瘤骨转移提供了一个新的视角，与我们最初的假设相反，来自成骨细胞肿瘤的外泌体诱导破骨细胞分化，此外还提出了前列腺癌骨转移的潜在治疗靶点。