结肠癌外泌体诱导的肝星状细胞活化在结肠癌肝转移中的作用及机制研究

Fine-tuned crosstalk between host microenvironment and disseminated cancer cells is required for successful colonization of a distant organ. The recruitment and activation of hepatic stellate cells (HSCs) are found around colon metastases in the liver, however, mechanism underlying the interaction between colon cancer cell and HSC remains obscure. In previous study, we found that colon cancer cells co-cultured with HSCs exhibited enhanced proliferation, and exosomes derived from liver metastatic colon cancer cells could trigger HSCs activation, suggesting a crosstalk between colon cancer cells and HSCs. In this project, we will further investigate the role of tumor-derived exosomes in HSC activation and its effect on colon cancer liver metastasis by using exosome-related techniques and in vivo liver metastasis model. Furthermore, small RNA-seq will be used to identify “critical miRNA” responsible for exosome-mediated HSC activation, and cytokine array and molecular biology techniques will be used to investigate HSC-secreted “critical cytokine” and its downstream signaling. Moreover, the correlation between the “critical cytokine” and the activated pathway will be studied in clinical liver metastasis samples, and the amount of “critical miRNA” in plasma will be detected to evaluate its potential as a predictive and prognostic biomarker for colon cancer liver metastasis.

转移器官微环境与肿瘤细胞间的相互作用是肿瘤转移形成的关键环节。研究表明肝星状细胞（HSCs）在结肠癌肝转移灶周围显著活化，然而HSCs与结肠癌细胞间的调控机制尚不明确。前期研究中，我们发现与HSCs共培养能促进高转移结肠癌细胞的增殖能力，并且高转移结肠癌细胞分泌的外泌体能诱导HSCs活化，提示两者之间的相互调控作用。本项目将利用外泌体相关技术、肝转移模型等，深入研究结肠癌细胞分泌的外泌体对HSCs的活化作用及后者在结肠癌肝转移中的作用。通过外泌体小RNA测序、细胞因子芯片等，探明结肠癌外泌体中活化HSCs的“关键miRNA”、HSCs调控肝转移分泌的重要细胞因子及下游效应分子。利用结肠癌原位和肝转移临床样本、血清，验证重要细胞因子和效应分子的相关性，分析血清中“关键miRNA”表达水平与结肠癌患者肝转移发生、预后的相关性，探讨其作为结肠癌肝转移预测及预后判定血清学标志物的价值。

转移器官微环境与肿瘤细胞间的相互作用在肿瘤转移形成中具有重要作用，而肝星状细胞与结肠癌细胞间的调控机制尚不明确。本项目利用外泌体相关技术、结肠癌肝转移模型、肝转移临床样本等实验，揭示了结肠癌细胞通过外泌体中的mir-107促进肝星状细胞活化的作用与机制，明确了活化的肝星状细胞对结肠癌细胞定植的作用，探讨了mir-107作为预测结肠癌肝转移标志物的价值。研究结果为转移微环境与肿瘤细胞相互作用提供了理论和实验依据，并为结肠癌肝转移提供了新的治疗靶点和预测标志物。本项目资助获得的研究成果已发表SCI论文3篇，影响因子均在5.0以上；资助期间，项目负责人获批专利1项；培养博士后1名，协助培养硕士研究生2名。