外泌体miR-122表达下调通过激活RhoA/ROCK1通路参与胃癌腹膜转移的分子调控机制及潜在临床应用研究

Peritoneal metastasis (PM) is the most common distant metastasis site for advanced gastric cancer, also, the treatment of PM patients is very difficult and their prognosis is very poor. Therefore, it is urgent to find the mechanism of PM and propose therapeutic strategies. We found that exosomes from ascites of PM patients may convey "dialogue" between tumor cells and peritoneum and participate in the biogenesis of PM. Considering the lower expression of miR-122 and activation of RhoA/ROCK1 pathway in exosomes from PM ascites, we speculate that exosome miR-122 downregulation gets involved in PM occurrence through activating the RhoA/ROCK1 pathway. .Based on the above hypothesis, this study is to identify ability of exosomes in ascites to facilitate migration and invasion, and to search for exosome miRNAs and key regulatory pathways or molecules that work in PM by transcriptomics and proteomics. The function and mechanism experiments will be conducted in cell lines，primary ascites tumor cells and animal models. This study aims to determine whether exosome miR-122 and RhoA/ROCK1 pathway participate in PM molecular regulation network. Finally, the possibility of PM treatment by using exosomes containing miR-122 or inhibitors of RhoA/ROCK1 pathway are revealed in order to provide important clues for clinical treatment.

腹膜转移(peritoneal metastasis, PM)是晚期胃癌最易发生的远处转移部位，PM患者是胃癌中治疗最棘手、预后最差的一类，亟需明确PM发生机制并提出治疗策略。我们研究发现，PM患者腹水外泌体可能在肿瘤细胞与腹膜之间传达“对话”参与PM发生，PM腹水外泌体中miR-122表达下调且RhoA/ROCK1通路激活，我们推测外泌体miR-122下调通过激活RhoA/ROCK1通路参与PM发生。.本课题围绕上述假说，利用PM患者腹水，明确腹水外泌体的促转移侵袭能力，利用转录及蛋白质组学探索参与PM发生的外泌体miRNAs及关键调控通路或分子，并在细胞系、腹水原代肿瘤细胞及动物体内进行功能与机制验证，阐释外泌体miR-122及RhoA/ROCK1通路参与PM的分子调控网络，揭示负载miR-122外泌体或RhoA/ROCK1通路抑制剂在PM治疗中的可行性，为临床治疗提供重要线索。

腹膜转移(peritoneal metastasis, PM)是晚期胃癌最易发生的远处转移部位，PM患者是胃癌中治疗最棘手、预后最差的一类，亟需明确PM发生机制并提出治疗策略。我们研究发现，PM患者腹水外泌体可能在肿瘤细胞与腹膜之间传达“对话”参与PM发生，PM腹水外泌体中miR-122表达下调且RhoA/ROCK1通路激活，我们推测外泌体miR-122下调通过激活RhoA/ROCK1通路参与PM发生。.本课题围绕上述假说，利用PM患者腹水，明确腹水外泌体的促转移侵袭能力，利用转录及蛋白质组学探索参与PM发生的外泌体miRNAs及关键调控通路或分子，并在细胞系、腹水原代肿瘤细胞及动物体内进行功能与机制验证，阐释外泌体miR-122及RhoA/ROCK1通路参与PM的分子调控网络，揭示负载miR-122外泌体或RhoA/ROCK1通路抑制剂在PM治疗中的可行性，为临床治疗提供重要线索。