miR-3188靶向mTOR变异环路在鼻咽癌中介导FOXO1抑制细胞生长以及诱导放化疗增敏

miR-3188 was significantly downregulated in NPC tissues and cells. Preliminarily analysis of function and molecular basis for miR-3188 indicated that miR-3188 directly targeted mTOR suppressing PI3K/AKT signal and c-Jun, which feedbackly stimulated the expression of miR-3188 and finally inhibited the transition of cell cycle and cell growth in NPC. These results preliminarily suggested miR-3188 as a potential tumor-suppressive miRNA in NPC. Interestingly, FOXO1 as a classical tumor suppressor not only induced the miR-3188 expression, but also suppressed the expression of PI3K/AKT/c-Jun signal and mTOR. This result hinted that miR-3188-mediated abnormal loop through suppressing PI3K/AKT signal and c-Jun and feedbackly inducing its expression modulated by FOXO1. Further studies will be performed as follow: 1) Confirming the role of miR-3188 in suppressing cell growth and detailed molecular mechanism in NPC. 2) Validating the feedback loop of miR-3188-mediated directly targeting of mTOR modulating PI3K/AKT/c-Jun signal and feedbackly inducing its expression modulated by FOXO1 participated in FOXO1-mediated inhibition of NPC pathogenesis.3) Effect of miR3188 on proliferation and radiochemosensitivity of NPC cells .

miR-3188在鼻咽癌组织和细胞中表达明显下调。前期研究表明，miR-3188在鼻咽癌中直接靶击mTOR，抑制PI3K/AKT信号和c-Jun转录因子，反馈诱导其表达，从而抑制了细胞周期转化和增殖，该结果显示miR-3188在鼻咽癌中发挥了候选抑癌基因的作用。有意思的是，FOXO1作为一个经典的抑癌基因，在鼻咽癌中不但诱导miR-3188表达，而且也抑制PI3K/AKT/c-Jun和mTOR表达。该结果提示miR-3188通过抑制mTOR/PI3K/AKT/c-Jun信号通路反馈诱导其表达形成的变异环路能被FOXO1调控。进一步研究如下：1）确证miR-3188在鼻咽癌中抑制细胞生长和具体的分子机制；2）验证miR-3188在鼻咽癌细胞中直接靶击mTOR并诱导其表达形成的变异环路能被FOXO1调控；3）探讨miR-3188在鼻咽癌中介导FOXO1抑制肿瘤细胞生长过程中对放化疗增敏影响。

在本研究中，我们阐明了miR-3188抑制鼻咽癌（NPC）发生发展的发病机理及其分子机制。首先，miR-3188不仅抑制了细胞周期G1向S期转化和增殖，并且显着延长了荷瘤小鼠的生存时间，增加了细胞对5-FU药物的化疗敏感性。机理研究表明，miR-3188可以直接靶向mTOR通过p-PI3K/p-AKT/c-Jun失活并诱导其自身表达。该反馈回路进一步抑制了通过p-PI3K/p-AKT/p-mTOR途径的细胞周期信号传导。从而形成了一条负性反馈环路，参与调控鼻咽癌的进程。除此之外，我们还观察到miR-3188直接靶向mTOR是由FOXO1抑制p-PI3K/p-AKT/c-Jun信号介导的，并且FOXO1通过PI3K/AKT/c-Jun信号通路诱导miR-3188的表达并抑制鼻咽癌细胞的增殖。在临床样品中，确认miR-3188表达下调对鼻咽癌患者是一个不利的预后因素。我们的研究表明，miR-3188直接靶向mTOR以刺激其自身表达，并参与FOXO1介导的细胞生长抑制和化疗耐药。