TCF-4介导的miR-328通过KIF23调控胶质瘤细胞增殖的机制

异常表达的miRNA与胶质瘤患者生存期密切相关。我们前期发现miR-328是胶质瘤患者预后评估的独立性因素，但其在胶质瘤恶性进展中的作用机制尚不明确。进一步研究发现miR-328通过间接调控KIF23表达抑制胶质瘤细胞增殖；TCF-4是miR-328的靶基因，而KIF23启动子区有TCF-4转录结合部位。据此我们提出假说：胶质瘤中miR-328低表达后通过靶向调控TCF-4影响β-catenin/TCF-4复合体转录活性，进而调节原癌基因KIF23表达，诱导细胞增殖失控。为验证该假说，本课题拟通过胶质瘤细胞、组织和裸鼠模型，采用生物信息学、基因转染、荧光素酶及Chip等方法，从分子、细胞、组织及动物水平多层次阐明胶质瘤中miR-328通过调控KIF23表达诱导细胞增殖失控的分子机制。本研究将从miR-328、KIF23这两个新视点为揭示胶质瘤的发病机理奠定基础，并为分子靶向治疗提供新思路。

Abnormal expression of miRNAs is associated with the overall survival time in glioma patients. Our previous study showed that miR-328 can serve as an independent prognostic biomarker for glioblastoma patients. However, the molecular mechanisms of miR-328 in the malignant progression of glioma have not yet been elucidated. Further research indicated that miR-328 suppresses glioma cell proliferation by inhibiting KIF23 expression, and TCF-4 is the direct target gene of miR-328, furthermore, KIF23 might transcriptional regulated by TCF-4. Thus, we propose a hypothesis that miR-328 modulates the β-catenin/TCF-4 transcriptional activities by inhibiting its target gene TCF-4 expression, which further suppresses the oncogene KIF23 expression to induce cell proliferation in glioma. To verify the above hypothesis, we will explore the functional role and analyze the regulation relationship among miR-328, TCF-4, KIF23 in glioma cell and clinical specimens via a series of molecular biology avenues in vitro and in vivo, such as bioinformatics, cell transfection, luciferase reporter assay, co-immunoprecipitation, xenograft, et al. In summary, the present study aims to investigate the role of miR-328、KIF23 in gliomagenesis and evaluate the possibility of miR-328 act as a potential target for glioma therapy.