SOX17/miR-371-5p/SOX2信号轴调控结直肠癌细胞侵袭、转移及肿瘤干性的分子机制

MiR-371-5p，a novel metastasis-associated miRNA，was screened from colorectal carcinoma tissue microarray．It was showed that down-regulation of miR-371-5p could promote colorectal carcinoma cell proliferation，invasion and sphere forming abilities in vitro and enhance its abilities of metastasis to lymphonodus and liver in vivo in our previous study．Based on the bioinformatic analyses and preliminary experiments，we proposed a hypothesis that SOX17/miR-371-5p/ SOX2 signaling axis could regulate invasion，metastasis and stem cell properties of colorectal carcinoma cell．In the study，miRNA transfection，interference and experiments in vitro and in vivo and so on are performed to validate the hypothesis，① to confirm that miR-371-5p is targeted by transcription factor SOX17，② to prove that SOX2 mediates the effect of miR-371-5p directly on invasion，metastasis and regulation of stem cell properties of colorectal carcinoma cell，③ to test and verify the role of SOX17/miR-371-5p/ SOX2 signaling axis in the progression of colorectal carcinoma and regulation of cancer stem cell properties and investigate the relation between the axis and Wnt/β-Catenin signaling pathway．In our study，we aim to reveal a novel regulatory mechanism in colorectal carcinoma and provide a novel theory and gene targets for clinical intervention of invasion and metastasis of colorectal carcinoma．

miR-371-5p是我们从芯片中筛选出的一个新的转移相关miRNA。预实验发现，下调miR-371-5p的表达能促进结直肠癌细胞体外生长、侵袭及成球能力并增强其向淋巴结和肝脏转移的能力。基于生物信息学分析和预实验结果，我们提出SOX17/miR-371-5p/SOX2信号轴调控结直肠癌细胞侵袭、转移及肿瘤干性的假说。本研究拟用miRNA转染、干扰及体内外等实验验证该假说:①确定SOX17是miR-371-5p的转录因子；②证实SOX2直接介导miR-371-5p在结直肠癌中的功能；③检验SOX17/miR-371-5p/SOX2轴在结直肠癌演进和干性调控中的作用并探讨其与Wnt/β-Catenin信号通路之间的关系。旨在结直肠癌中揭示一个新的调控机制，为抗结直肠癌侵袭和转移提供新的理论基础和基因靶点。

世界范围内，结直肠癌是女性第二常见和男性第三常见的恶性肿瘤,它是肿瘤相关死亡的主要原因之一。肿瘤的转移是对结直肠癌患者生存最大的威胁。因此，揭示转移相关分子对于开发新的治疗结直肠癌策略十分重要。miR-371-5p是我们从芯片中筛选出的一个新的转移相关miRNA。前期我们发现下调miR-371-5p的表达能促进结直肠癌细胞体外生长、侵袭及成球能力并增强其向淋巴结和肝脏转移的能力。基于生物信息学分析和预实验结果，我们提出SOX17/miR-371-5p/SOX2信号轴调控结直肠癌细胞侵袭、转移及肿瘤干性的假说。本项目利用miRNA转染、干扰及体内外等实验验证该假说:①确定SOX17是miR-371-5p的转录因子；②证实SOX2直接介导miR-371-5p在结直肠癌中的功能；③检验SOX17/miR-371-5p/SOX2轴在结直肠癌演进和干性调控中的作用并探讨其与Wnt/β-Catenin信号通路之间的关系。本项目的主要研究结果显示：①SOX17在转录水平促进miR-371-5p的表达；②SOX2是miR-371-5p下游的直接的功能靶点并介导其对结直肠癌细胞生物学行为的作用；③SOX17/miR-371-5p/SOX2轴的异常促进结直肠癌细胞的上皮间质转化、侵袭及转移能力并增强结直肠癌细胞的肿瘤干性特征；④SOX17/miR-371-5p/SOX2轴的异常促进β-Catenin的核转位并增强了Wnt/β-Catenin信号通路的活性。本项目识别了miR-371-5p作为一个肿瘤抑制miRNA参与到结直肠癌进程的调控中，阐明了一个新的包括SOX17、miR-371-5p及SOX2的轴调控结直肠癌的EMT、肿瘤干性及转移行为，为抗击结直肠癌转移提供了潜在的分子靶点。