昆布多糖靶向上皮细胞间充质转化增敏减毒及抗肿瘤耐药研究

The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype; it has a profound impact on cancer progression and metastasis. It is found to be widely correlated with a loss of sensitivity and an increase in resistance to various conventional chemotherapies, including cisplatin, carboplatin, paclitaxel, gemcitabine, and 5-fluorouracil, but also with the acquired resistance to EGFR-TKIs as gefitinib. J201 is a kind of sulfated polysaccharide extracted from marine algea, which had been proven to inhibit the development of pulmonary fibrosis by intervening the expression of inflammatory cytokines and body immune system. Recent study shows that J201 can significantly alter EMT effect of lung cancer cells induced by TGF-β. In this study, multiple cells and animals models are used to study the effect of J201 to modulate the EMT process and restore sensitivity of lung cancer cells to chemotherapy and EGFR-TKIs, which will gave way to the study of combination of lamilarin polysaccharide with chemotherapeutic drugs or EGFR-TKIs. The result of the investigation will provide laboratory data for the further development of lamilarin polysaccharide and its theoretical support for rational clinical application.

上皮细胞间充质转化（EMT）与肿瘤的发生、浸润和转移密切相关，尤其值得关注的是，铂类等化疗药物和易瑞沙等分子靶向药物的获得性耐药的产生与EMT转化紧密相关。J201是本课题组以昆布对肺纤维化的中医药辩证治疗理论为启迪筛选获得的海洋硫酸多糖类提取物，其通过影响炎性因子的表达以及机体免疫系统，从而明显抑制肺间质纤维化，进一步研究发现， J201能够明显影响TGF-β诱导的肺癌细胞的EMT效应。本课题拟综合运用现代生物学及药理学技术手段，从"确证药效特性"与"关注耐药机制"两个功能视角同步出发，以EMT转化为切入点，采用多种细胞以及动物体内模型，进一步确证昆布多糖逆转EMT转化、抑制肿瘤的作用；同步，关注耐药机制的克服，开展昆布多糖与化疗药物及分子靶向药物的联合用药研究。预期研究成果将为昆布多糖的进一步开发提供实验证据，为临床的合理应用提供理论支持。

肿瘤的转移是导致肿瘤患者死亡的重要因素。TGF-β可通过诱导肿瘤细胞的EMT转化，而从促进肿瘤的转移及其耐药。我们前期发现，昆布多糖J201可通过靶向TGF-β，从而抑制肺纤维化的发生。本课题中我们发现，J201能够通过抑制TGF-β/Smad 信号通路的活化，从而逆转细胞的EMT转化，抑制肿瘤细胞的肺转移。进一步的研究我们也发现，J201能够明显下调荷瘤小鼠肿瘤与脾组织中调节性T细胞（Treg）的细胞数，增加CD8+T细胞的浸润，从而发挥拮抗肿瘤转移的作用。联合用药研究发现，化疗药物浓度在IC50以下时，J201具有一定的增强化疗药物药效的作用，而在IC50以上时，J201的增敏作用则不明显。