SNHG6-003调控外泌体促进肝癌细胞侵袭转移的分子机制

我们前期研究结果发现SNHG6-003在肝癌发生发展中发挥重要作用（Oncogene. 2017）。近期，我们预实验结果表明：SNHG6-003促进肝癌细胞外泌体释放而增强细胞侵袭和迁移能力；SNHG6-003调控的外泌体可诱导肝星状细胞增殖活化，降低正常肝细胞对葡萄糖的利用，诱导正常内皮细胞间质化，从而改造肿瘤微环境。基于前期研究结果，本项目拟深入探讨SNHG6-003调控外泌体促进肝癌细胞转移的分子机制。首先，阐明SNHG6-003促进外泌体释放的分子机制；其次，探讨SNHG6-003调控的外泌体对肿瘤微环境和转移前微环境的影响，以及微环境中的间质细胞对肿瘤细胞的正反馈作用；最后，探讨阻断肝癌细胞SNHG6-003对肿瘤微环境和转移前微环境的影响。据此，阐明SNHG6-003调控外泌体促进肝癌侵袭转移的分子机制并为肝癌治疗提供新的靶点。

We have demonstrated that the expression of SNHG6-003 has been dysregulated in hepatocellular carcinoma (HCC) and may serve as novel prognostic markers and therapeutic targets (Oncogene, 2017). Recently, our preliminary data showed that SNHG6-003 promoted HCC cell invasion and migration by inducing exosomal secretion. The exosomes secreted by SNHG6-003-overexpressed cells activated hepatic stellate cell (HSC), suppressed glycolytic metabolism and glucose consumption in normal cells, and induced endothelial-mesenchymal transition (EndoMT). SNHG6-003 may also play a role in the establishment of a “pre-metastatic niche” and in turn facilitate cancer cell proliferation and metastasis. Thus, based on our data, we will elucidate the exact role and reliability of SNHG6-003-induced exosomes in tumor invasion and metastasis. Firstly, we will investigate the molecular mechanism by which SNHG6-003 control exosome synthesis and release. Secondly, we will explore how SNHG6-003-induced exosomes modulate tumor environment and pre-metastatic niche. We also explore the positive feedback of the stromal cells on tumor cells. Lastly, we will investigate the effect of blocking SNHG6-003 in HCC cells on tumor environment and metastasis. In conclusion, in this project, we aim to clarify the biological function and molecular mechanism in which SNHG6-003-induced exosomes promote HCC metastasis, which might provide new biomarkers and targets for the treatment of cancer.