VPA药物通过Sp1/TRIM24/HDAC1复合物诱导miR-3913-5p/3p的表达促进结直肠癌细胞凋亡

研究表明，小分子RNA与肿瘤发生发展关系密切。用测序技术对VPA(Valproic acid)处理肠癌细胞行miRNAs差异表达分析，筛选到上调的miR-3913-5p和miR-3913-3p分子，并证实它们在结直肠癌(CRC)中低表达；用生信学等方法发现：TRIM24是miR-3913-5p/3p共同靶基因；质谱分析显示TRIM24、Sp1与HDAC1三个蛋白两两互作，形成复合物，可影响前体miR-3913的转录。因此提出假设：在结直肠癌中，miR-3913-5p/3p的降低可受到上游转录因子Sp1负向调控，导致TRIM24和HDAC1表达升高；HDAC抑制剂VPA可通过Sp1-TRIM24-HDAC1复合物调控miR-3913-5p/3p表达，促进细胞凋亡。本研究拟探究miR-3913-5p/3p与TRIM24基因靶标关系及上下游分子网络机制，可为CRC早期诊断，预后及治疗提供新思路。

MicroRNA plays an important role in tumorigenesis and development. In our preliminary studies, different expression profiles of miRNAs were first screened from colorectal cells with or without valproic acid (VPA)-treatment by human miRNA-sequencing technology. MiR-3913-5p and miR-3913-3p are our interest targets, both of which were downregulated in colorectal cancer compared to normal tissues. TRIM24 was found to be a target gene of both miR-3913-5p and miR-3913-3p by bioinformatics analysis. Moreover, a complex of three molecules including TRIM24, Sp1 and HDAC1 were found by liquid chromatography-tandem mass spectrometry to be able to affect the transcriptional regulation of the precursor miR-3913. Therefore, it is hypothesized that downregulation of miR-3913-5p/3p by the upstream transcription factor Sp1 enhances the expression of TRIM24 and HDAC1; on the other hand, VAP, the HDAC inhibitor, is able to regulate the transcriptional activity of the complex of Sp1-TRIM24-HDAC1, resulting in the upregulation of miR-3923-5p/3p and promoting cell apoptosis in colorectal cancer. The aim of this study is to observe the relationship between miR-3913-5p/3p and TRIM24, and then explore their potential molecular mechanisms, which could provide new strategies for the early diagnosis, prognosis and treatment of colorectal cancer.