GEFT诱导 lncPSMA8-1差异表达调控miR-144-3p/mTOR促进横纹肌肉瘤进展的分子机制研究

横纹肌肉瘤（Rhabdomyosarcoma，RMS）尤其是儿童患者预后差。我们前期研究显示GEFT基因过表达与RMS临床分期和远处转移密切相关，并可能通过RhoGTPases-mTOR发挥癌基因作用。进一步研究发现GEFT能上调lnc-PSMA8-1表达，而后者是调控mTOR的关键因子，且可能通过结合miRNA解除其对mTOR mRNA的抑制。因此，我们推测GEFT通过上调lnc-PSMA8-1表达竞争性结合miR-144-3p解除其对靶基因mTOR的抑制，促进RMS进展。本项目在运用lncRNA芯片筛选并鉴定GEFT靶向调控lnc-PSMA8-1的基础上；通过诱导或阻断lnc-PSMA8-1、miR-144-3p、mTOR表达，探讨三者之间的关系，然后，构建动物模型阐明GEFT调控lnc-PSMA8-1-miR-144-3p-mTOR通路在RMS进展中的作用机制，为其靶向治疗奠定基础。

Rhabdomyosarcoma (RMS) is the most common childhood malignant soft tissue tumor. The prognosis of the children patients with rhabdomyosarcoma is poor. Our previous studies have shown that over expression of GEFT was closely related with clinical stages and metastasis of patients with rhabdomyosarcoma. GEFT may play an oncogene role through Rho GTPases-mTOR. Recent studies have shown that lncRNAs are key factors regulating the expression of mTOR and are expected to become new targets for cancer therapy. Further studies have shown that GEFT can up-regulate the expression of lnc-PSMA8-1, which is a key factor in regulating the expression of mTOR, and may inhibit downstream mTOR mRNAs by competitive binding to microRNAs. Therefore, we hypothesize that GEFT can relieve the inhibition of downstream target gene mTOR by up-regulating the expression of lnc-PSMA8-1 and binding miR-144-3p, thus affecting the progress of RMS. To verify this hypothesis, firstly, we plan to analyze screen and identify differentially expressed lncRNAs by using lncRNA chips. Secondly, by inducing or blocking the expression of lnc-PSMA8-1, miR-144-3p and mTOR, the targeting relationship among them will be explored in RMS. Lastly, we will construct an animal model to elucidate the roles and mechanisms of GEFT in the regulation of lnc-PSMA8-1-miR-144-3p-mTOR pathway in the progress of RMS, and we will lay a foundation for metastasis prevention and targeted therapy of rhabdomyosarcoma.