核基质结合因子SAFB在结直肠癌发生发展过程中的作用及分子机制研究

Colorectal cancer (CRC) is one of the most commonly digestive malignant tumor, which has gravely affected people's health. Therefore, it is necessary for us to further investigate the pathogenesis of colorectal cancer, and to development effective treatment. Scaffold attachment factor B (SAFB) is a multifunctional protein implicated in a variety of cellular processes including regulation of transcription, stress response, cell growth and apoptosis, and is associated with tumorigenesis to some certain extent. Our previous work showed that downregulation of SAFB may be involved in the development of colorectal cancer, but the function, the related molecular mechanism and the upstream regulation of SAFB still remain unknown. In this project, some experiments in vivo and in vitro, including MTT, colony formation, soft-agar colony formation, flow cytometry, TUNEL staining, the angiogenesis of chick chorioallantoic membrane ( CAM ) assay and xenograft model in nude mice, will be used to measure proliferation, apoptosis and angiogenesis of colorectal cancer cells treated with SAFB. Then we will investigate the related molecular mechanism of SAFB by gene set enrichment analysis (GSEA), chromatin immunoprecipitation assay (CHIP), co-immunoprecipitation (Co-IP). Finally, upstream regulation of SAFB by microRNAs will be detected through the bioinformatics analysis, dual luciferase reporter gene assay, westernblot and real-time PCR (RT-PCR). In a word, the study is hoped to provide theoretical evidence for individualized treatment and development of molecule-targeting agents of colorectal cancer.

结直肠癌是一种常见的消化系统恶性肿瘤，严重危害人类身体健康，深入研究结直肠癌的发病机制、开发有效的治疗措施具有重要的临床价值。SAFB调节基因转录，抑制细胞增殖，促进细胞凋亡，并与肿瘤发生具有一定的关系。本课题前期实验表明SAFB表达下调可能参与结直肠癌的发生发展，但SAFB在结直肠癌中的作用、分子机制和上游调控尚不清楚。本研究拟通过MTT、平板克隆形成、流式细胞技术、TUNEL染色、鸡胚尿囊膜血管生成和裸鼠皮下成瘤等体内外实验检测SAFB对结直肠癌细胞增殖、凋亡和血管生成的影响；通过GSEA基因富集分析、染色体免疫共沉淀、免疫共沉淀研究SAFB在结直肠癌发生发展过程中的分子机制；通过生物信息学分析、荧光素酶报告基因、westernblot和RT-PCR探讨在结直肠癌发生过程中microRNAs对SAFB的调控作用。通过本研究以期为结直肠癌的个体化诊疗和靶向药物的开发提供一定的理论依据。

结直肠癌是一种常见的消化系统恶性肿瘤，严重危害人类身体健康，深入研究结直肠癌的发病机制、开发有效的治疗措施具有重要的临床价值。SAFB调节基因转录，抑制细胞增殖，促进细胞凋亡，并与肿瘤发生具有一定的关系。本课题前期实验表明SAFB表达下调可能参与结直肠癌的发生发展，但SAFB在结直肠癌中的作用、分子机制和上游调控尚不清楚。本研究结直肠癌组织中SAFB表达水平显著下调；SAFB的表达水平与结直肠癌的分化、Dukes分期、TNM分期、转移和预后等临床病理参数间呈负相关关系；SAFB通过靶向TAK1调控NF-κB信号通路的活性，进而调节结直肠癌细胞的发生、侵袭性和转移能力；miR-183通过直接靶向SAFB 的3'-UTR抑制其表达；在结直肠癌患者中SAFB的表达与miR-183、TAK1的表达及NF-κB信号通路下游效应分子MMP9、IL6、IL8及VEGF的表达均呈显著负相关关系。本研究有望为结直肠癌的个体化诊疗和靶向药物的开发提供一定的理论依据。