Exosomal lnc-CTBP1-AS1激活肝星状细胞促进胰腺癌肝转移的机制研究

肿瘤细胞分泌的外泌体通过其内容物介导原发性肿瘤细胞与不同器官间质细胞的双向作用被认为是肿瘤转移的重要机制。我们前期研究发现lnc-CTBP1-AS1在高转移性胰腺癌细胞分泌的外泌体中高表达，它以高转移性胰腺癌细胞分泌的外泌体为载体传递至肝星状细胞，进一步激活肝星状细胞并促进其迁移。据此我们提出假说：Exosomal lnc-CTBP1-AS1可以激活肝星状细胞促进胰腺癌肝转移。我们将运用功能缺失性和功能获得性研究、小鼠移植瘤模型等实验方法，1) 明确高转移性胰腺癌细胞分泌的外泌体与肝星状细胞激活及胰腺癌肝转移的相关性；2) 揭示高转移性胰腺癌细胞来源exosomal lnc-CTBP1-AS1在肝星状细胞激活中的作用及分子机制；3) 阐明高转移性胰腺癌细胞源exosomal lnc-CTBP1-AS1激活的肝星状细胞在胰腺癌肝转移中的作用。为胰腺癌肝转移提供新的治疗靶点。

Tumor-derived exosomes mediate the bilateral interaction between primary tumor cells and stromal cells in distinct organs by transporting information cargo is considered to be an important mechanisms of tumor metastasis. Our previous study showed that lnc-CTBP1-AS1 was highly expressed in exosomes secreted by high-metastatic pancreatic cancer cells. Lnc-CTBP1-AS1 can be delivered to hepatic stellate cells by exosome isolated from high-metastatic pancreatic cancer cells, further activating hepatic stellate cells and promoting its migration. Therefore, we propose that “Exosomal lnc-CTBP1-AS1 induces hepatic stellate cells activation to foster liver metastasis of pancreatic cancer”. we will use loss-of-function、gain-of-function and xenograft models, 1) to study the correlation between exosomes secreted by high-metastatic pancreatic cancer cells and hepatic stellate cell activation or pancreatic cancer liver metastasis; 2) to reveal the mechanism of high-metastatic pancreatic cancer cell derived exosomal lnc-CTBP1-AS1 in hepatic stellate cell activation; 3) to elucidate the role of hepatic stellate cells activated by high-metastatic pancreatic cancer cell derived exosomal lnc-CTBP1-AS1 in pancreatic cancer liver metastasis. Our study may provide a new promising therapeutic target for the liver metastasis of pancreatic cancer.