miR-195-5p调控eIF4E基因表达在宫颈癌发生中的作用机制研究

Eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting member of the eIF4F complex in eukaryotic translation and plays important roles in cell growth and maglinant transformation. Epigenetic alterations can affect the activity of eIF4E. However, to date, there have been no reports on microRNAs (miRNAs) that can regulate eIF4E expression in tumors. eIF4E is reported to be up-regulated in cervical cancer. To assess the role of eIF4E expression deregulation caused by miRNAs in cervical cancer, we performed the miRNAs prediction of eIF4E, and found that with the exception of miR-195-5p, none of the predicted miRNAs in miRNA target databases is known to be down-regulated in cervical cancer; Further study suggested an inverse correlation between miR-195-5p and eIF4E expression in cervical cancer cells; Moreover, our previous study indicated that the down-regulated miR-195-5p obviously promotes cell growth. Therefore, we provides the hypothesis that the aberrant less expression of miR-195-5p and consequent eIF4E up-regulation may contribute to cervical carcinogenesis. Base on the above results, we aim to investigate the role of eIF4E expression regulated by miR-195-5p in cell translation and cervical cancer pathogenesis through further functional analyses on the levels of clinic, cell and animal model, which will contribute to provide a significant theory support for new labelling indexes and treatment of cervical cancer.

eIF4E是真核细胞翻译过程的关键限速因子，在促进细胞生长、恶性转化中发挥重要作用。eIF4E活性可受表观遗传调节，但目前尚无有关肿瘤组织中eIF4E的miRNA调控研究。有文献报道eIF4E在宫颈癌中表达上调。为探讨miRNA调控eIF4E表达在宫颈癌发生中的作用机制，我们在众多被预测靶向eIF4E 3'-UTR的miRNAs中发现只有miR-195-5p在宫颈癌中表达下调，两者表达呈负相关；而miR-195-5p是我们前期研究证实的具有抑制细胞生长的重要miRNA，因此，我们推测miR-195-5p可能参与eIF4E的表达调控。本课题组拟在靶点鉴定基础上，进一步从宫颈肿瘤临床组织学分析、体外细胞学分析以及裸鼠体内移植瘤分析三个角度深入研究miR-195-5p靶向调控eIF4E对细胞翻译的影响，以及这一效应在宫颈癌发生中的作用机制，从而为宫颈癌新诊断标志物和治疗手段的建立提供理论依据。

eIF4E是真核细胞翻译过程的关键限速因子，在促进细胞生长、恶性转化中发挥重要作用。有文献报道eIF4E在宫颈癌中表达上调,但其机制尚不明确。为探讨miRNA调控eIF4E表达在宫颈癌发生中的作用机制，我们在众多被预测靶向eIF4E 3'-UTR的miRNAs中发现只有miR-195-5p在宫颈癌中表达下调，两者表达呈负相关；而miR-195-5p是我们前期研究证实的具有抑制细胞生长的重要miRNA，因此，我们推测miR-195-5p可能参与eIF4E的表达调控。本项目就miR-195-5p调控eIF4E表达在宫颈癌发生中的作用机制展开研究。我们在eIF4E 3'-UTR miR-195-5p靶位点鉴定的基础上，进一步研究发现miR-195-5p 靶向抑制 eIF4E 表达可以抑制宫颈癌 SiHa 细胞的帽依赖性翻译、细胞增殖、细胞克隆形成和侵袭力，促进细胞凋亡；裸鼠体内移植瘤分析结果显示miR-195-5p可以通过下调eIF4E表达抑制瘤体的生长。因此miR-195-5p是新的可以靶向抑制eIF4E的miRNA分子，miR-195-5低表达诱导的 eIF4E表达上调将有助于宫颈癌的发生，miR-195-5p通过靶向调控eIF4E表达在宫颈癌中发挥肿瘤抑制因子的作用。我们的研究有利于进一步揭示宫颈癌的发病机理，从而做到早诊断、早治疗，提高患者生存率。