脾虚内环境exosome--integrins通路对肝癌侵袭和转移特性的影响

The internal environment of spleen deficiency is closely related to the occurrence and development of hepatocellular carcinoma. The clinical study found that improving the internal environment of spleen deficiency is effective for the prevention and treatment of hepatocellular carcinoma, but its biological basis is not clear. In previous studies, we found that the obstacle of transport and transformation of dampness in spleen deficiency environment is an important cause of changes in the body environment, and is closely related to the occurrence and development of hepatocellular carcinoma. Our pre experiment found those hepatoma cells had stronger migration and invasion ability which had been stimulated by exosome of hepatocellular carcinoma with spleen deficiency mice, the expression of integrin (integrin, ITG) ITGβ1 and ITG β5 significantly increased in the liver cancer tissues of mice with spleen deficiency, and the integrin could lead to the targeting of the exosome. We speculate that the changes in the exosome-integrins pathway in the spleen deficiency environment may be closely related to the invasion and metastasis of hepatocellular carcinoma, we put forward the hypothesis of "the close relationship between the exosome-integrins pathway of spleen deficiency environment and the invasion and metastasis of liver cancer" .To confirm this hypothesis, we will establish a mouse model for hepatocellular carcinoma with spleen deficiency, explore the molecular mechanism of the change of exosome-integrins pathway in the spleen deficiency environment and the invasion and metastasis of liver cancer by detecting the changes of exosome-integrins pathway in hepatocellular carcinoma mice with spleen deficiency and control hepatocellular carcinoma mice, hope to provide a new strategy for traditional Chinese medicine in preventing and treating hepatocellular carcinoma.

脾虚内环境与肝癌发生发展关系密切。临床研究发现改善脾虚内环境对防治肝癌有效，但其生物学基础尚不明确。在前期研究中，我们发现脾虚湿浊转运障碍所致内环境变化是肝癌发生发展的重要原因，预实验发现脾虚小鼠肝癌外秘体（exosome）刺激后的肝癌细胞具有更强的迁移侵袭能力, 整合素（integrin，ITG）ITGβ1、ITGβ5在脾虚小鼠肝癌组织中表达明显升高，而整合素可导致外泌体的靶向性，我们推测脾虚内环境exosome-integrins通路变化可能与肝癌侵袭转移密切相关，提出“脾虚内环境exosome-integrins通路变化—肝癌侵袭转移特性相关”假说。为证实这一假说，我们将建立脾虚肝癌小鼠模型，通过检测脾虚肝癌小鼠和对照肝癌小鼠exosome-integrins通路变化，探讨脾虚内环境exosome-integrins通路变化对肝癌侵袭转移特性的影响，以期为中医药防治肝癌提供新的策略。

脾虚内环境与肝癌发生发展关系密切，尤其在肝癌侵袭转移中起着重要作用，但是具体机制目前还未知。本课题在中医脾胃理论指导下，开展了脾虚内环境通过exosome-integrins通路变化对肝癌侵袭转移影响的研究，发现：. ①脾虚基础的原位移植肝癌小鼠模型和药物诱导肝癌模型型的成瘤率、肿瘤体积显著高于对照组，进一步通过检测脾虚肝癌小鼠和对照肝癌小鼠的exosome-integrins通路变化，证实脾虚内环境促进小鼠肝癌的恶性进展这一过程与exosome-integrins相关。脾虚肝癌小鼠外泌体在体外和体内均增强了肝癌细胞的侵袭和转移，外泌体介导的整合素integrinsα1、integrinsβ1和integrinsβ5的上调在其中起着重要作用，提示为脾虚内环境“土壤”中exosome-integrins通路导向性促进肝癌侵袭转移。. ②对原位移植肝癌小鼠模型血浆中提取的外泌体进行miRNA测序，测序结果表明15个miRNAs在脾虚肝癌组差异表达，其中9个上调，6个下调。差异表达miRNAs靶向的mRNAs富集的通路与转移相关。说明脾虚内环境来源的状态下外泌体可能通过miRNA-mRNA轴促进肝癌转移。. 以上研究提示脾虚内环境exosome-integrins通路变化靶向性促进了肝癌侵袭转移，这些研究结果将为中医药治理脾虚内环境防治肝癌提供新的治疗策略，促进中医脾胃理论的完善和发展，具有重要的理论意义和临床应用价值。