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

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.

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。

肿瘤细胞分泌的外泌体可以通过其携带的内含物调控转移前微环境的形成。胰腺癌作为一种易发生转移的恶性肿瘤，外泌体介导其发生远距离转移的作用及机制尚不明确。本项目研究发现，高转移性胰腺癌细胞分泌的外泌体可以被传递至肝星状细胞LX-2并促进其激活，激活的肝星状细胞可以通过促进炎性因子IL-6和胞外基质FN的表达，营造适合转移的肝脏微环境，反过来促进胰腺癌的肝转移。机制研究表明，lncRNA TTTY15和BRAP在高转移性胰腺癌细胞分泌的外泌体中高表达，且TTTY15和BRAP可以随外泌体传递至肝星状细胞。下调肝星状细胞LX-2中TTTY15和BRAP的表达显著抑制肝星状细胞的激活及IL-6和FN的表达。同时研究还表明，TTTY15与BRAP之间存在较强的结合能力，TTTY15通过影响BRAP的表达来影响肝星状细胞的激活，进而影响胰腺癌的肝转移。以上结果表明高转移能力的胰腺癌细胞分泌的外泌体可以通过携带lncRNA TTTY15和BRAP促进肝星状细胞的激活，反过来促进胰腺癌的肝转移。提示lncRNA TTTY15可能成为胰腺癌肝转移的一个新的治疗靶点。