miR-500a-5p在结直肠癌中的功能及其分子网络调控机制的研究

中国是结肠癌发病大国，其发病率逐年上升,虽然治疗手段有所改观，但近年来五年生存率无明显提高，发病和转移机制有待于进一步研究。转录因子和miRNA作为两种关键的调控因子在转录和转录后水平调控中发挥重要作用。预实验发现：miR-500a-5p在结直肠癌组织和细胞株中表达下调；生物信息学提示HDAC2可能是miR-500a-5p的下游靶基因；文献显示，YY1在肿瘤中高度表达，我们发现miR-500a-5p启动子存在多个YY1结合位点。因此我们设想：在结直肠癌中，YY1高度表达引起miR-500a-5p表达的降低，进一步导致HDAC2表达的增高；抑制剂HDAC调节YY1/p300/HDAC2转录复合物活性，提高miR-500a-5p表达水平，促进细胞凋亡。本项目将在分子相互作用、细胞功能、动物实验模型和肿瘤病人组织标本相关性等四个层次上展开深入研究，完成后对明确肿瘤的发生发展机制具有理论指导意义。

Colorectal cancer is a common malignant tumor in China. Its incidence has increased every year. Although the treatment methods are continuously improving, but there is no obvious improvement of the survival rate, which need further studies of the tumorigenesis and metastasis. Transcription factors and miRNA play key roles in both of transcriptional and post-transcriptional regulation. In our preliminary data, miR-500a-5p is downregulated in both colorectal cancer tissues and cell lines. Bioinformatics analysis indicates that HDAC2 may be a target gene of miR-500a-5p. It is reported that YY1 is overexpressed in several of malignant tumors. We show that there are several of YY1-binding elements in the promoter sequence of miR-500a-5p. Therefore, here are our hypotheses: YY1-overexpression induces the decrease of miR-500a-5p thus results in the overexpression of HDAC2 in colorectal cancer; inhibitor of HDAC regulates the transcription activity of YY1/p300/HDAC2 complex, increase miR-500a-5p expression level and promotes cell apoptosis. This proposal will be applied in cell lines, nude mice and colorectal cancer specimens, which is expected to apply the theoretical significance of tumorigenesis and development of colorectal cancer.