抑癌基因PDCD4调控miR-184和miR-374a抑制鼻咽癌生长及促进凋亡

Our previous preliminary investigation suggested that PDCD4 was taken as a tumor suppressor participating in the pathogenesis of nasopharyngeal carcinoma(NPC) through suppressing cell growth and promoting cell apoptosis. miRNA array and qPCR were used to examine the diffenentially expressed miRNAs in NPC cells with stably knocking down the expression of PDCD4, and miR-184 and miR-374a were shown to be significantly downregulated. We speculated that miR-184 and miR-374 were invovled in the regualtion of PDCD4-mediated cell growth and apoptosis in NPC.Therefore, further studies will be performed as follow: 1) Identifying PI3K/AKT/ C-JUN pathway mediated by PDCD4 to control the expression of miR-184 and miR-374a. 2) Validating transcription factor C-JUN to control the expression of miR-184 and miR-374a through directly regulating their promoter.3)Confirming miR-184 and miR-374a as tumor-suppressive roles in NPC, which inhibited cell gorwth and/or stimulating cell apoptosis; 4) Confirming miR-184 directly targeting C-MYC and BCL2 as well as miR-374a directly targeting C-MYC and/or CCND1, which participated in PDCD4-mediated pathway of suppressing cell growth and/or promoting cell apoptosis in NPC.

在前期研究中，我们发现PDCD4在鼻咽癌中抑制细胞生长并促进细胞凋亡而参与了鼻咽癌发病过程。miRNA芯片和qPCR检测发现，在鼻咽癌细胞中抑制PDCD4表达后miR-184和miR-374a表达显著下调。我们推测PDCD4通过这两个miRNAs参与了对鼻咽癌的生长与凋亡的调控。进一步的工作将从如下方面开展：1）明确PDCD4通过PI3K/AKT/C-JUN调节miR-184和miR-374a表达；2）验证转录因子C-JUN直接调节miR-184和miR-374a启动子影响它们表达；3）验证miR-184和miR-374a在鼻咽癌中抑制细胞生长和/或促进细胞凋亡。4）验证miR-184直接靶击癌基因C-MYC和BCL2以及miR-374a直接靶击癌基因C-MYC和/或CCND1参与PDCD4介导的抑制细胞生长和/或促进细胞凋亡通路。

研究背景：前期研究发现PDCD4在鼻咽癌中抑制细胞生长并促进细胞凋亡而参与了鼻咽癌发病过程。在鼻咽癌细胞中抑制PDCD4表达后发现miR-184和miR-374a表达显著下调。以此推测PDCD4通过这两个miRNAs参与了对鼻咽癌的生长与凋亡的调控。. 主要研究内容：明确PDCD4通过PI3K/AKT/C-JUN直接调节miR-184和miR-374a启动子影响它们表达；验证miR-184和miR-374a在鼻咽癌中抑制细胞生长和/或促进细胞凋亡的功能；验证miR-184直接靶击癌基因C-MYC和BCL2以及miR-374a直接靶击癌基因C-MYC和/或CCND1参与PDCD4介导的抑制细胞生长和/或促进细胞凋亡通路。. 重要结果及关键数据：本项目研究发现抑癌基因PDCD4可通过抑制PI3K/AKT信号下调c-Jun表达，降低c-Jun与miR-184启动子的结合，进而诱导miR-184表达。而miR-184进一步直接靶击BCL2和c-Myc，从而参与PDCD4诱导鼻咽癌细胞凋亡和抑制细胞生长的信号通路。此外，miR-374a可通过直接靶击CCND1失活pPI3K/pAKT/c-JUN信号通路，不仅通过下调c-JUN诱导了它自身的表达进而形成一个负反馈环路，同时也抑制了下游细胞周期进展及EMT相关信号。有趣的是，此过程能被PDCD4所失活的pPI3K/pAkt/c-Jun通路介导。相关数据已发表在Cell Death Disease及Oncogene杂志。. 科学意义：本研究揭示PDCD4调控miR-184靶向C-MYC和BCL-2抑制鼻咽癌细胞增殖和促进凋亡以及PDCD4通过介导miR-374a-CCND1-pPI3K/Akt-c-Jun环路抑制鼻咽癌细胞的生长、转移及对DDP的化疗抵抗。