基于Apelin与有丝分裂抑制剂的抗肝癌联合治疗新机制的研究

Clinically, malignant hepatocelluar carcinoma (HCC) is insensitive to chemotherapy, therefore it is urgent to study the mechanism of the drug resistance and develop new efficacious anti-HCC strategies. In the grant supported by Young Scientist Fund of NFSC which will be finished by the end of 2015, the applicant disclosed a novel molecular mechanism by which MPHOSPH1 and PRC1 proteins regulate mitosis and taxol resistance of HCC cells. We also demonstrated that the adipokine Apelin was downregulated in the HCC tissues of clinical samples, and Apelin peptide improved the anti-HCC effect of anti-mitotic agents, such as taxol and CA4, and brought synergistic effect against HCC by normalizing vessels of the HCC xenografts, which suggested that Apelin is a potential anti-HCC target. The mechanism study of its anti-HCC effect is thus of great value for exploring new efficacious anti-HCC therapeutic strategies. This proposal is aimed at clarifying the mechanism of reducing drug resistance of HCC from a new prospective, as well as the novel effect of Apelin on the development of HCC, and using various xenografted or transgenic animal HCC models, we plan to study the molecular mechanism of synergistic anti-HCC effect of Apelin and anti-mitotic agents combination, such as shRNA-MPHOSPH1/PRC1, which will provide new insight into drug targets searching and new anti-HCC strategies development.

临床上恶性肝癌对于化疗极不敏感，因此研究其药物抵抗机制并探索有效的抗癌新策略十分迫切。申请人在2015年即将结题的自然科学基金青年项目中，发现了MPHOSPH1和PRC1两个驱动蛋白调控肝癌细胞有丝分裂以及紫杉醇抵抗的新分子机制；申请人还发现在临床样本中脂肪因子Apelin在肝癌组织中表达下调，同时Apelin能通过促进肝癌血管正常化生长，提高CA4和紫杉醇等有丝分裂抑制类药物的抗癌效果并产生协同抗癌作用，是一个潜在的肝癌治疗新靶点，其抗癌机制对于探索有效的肝癌药物治疗新策略具有很好的理论研究价值。本项目将从该角度探索降低肝癌药物抵抗的新机制，深入研究Apelin在肝癌发生发展中所起的特殊作用，并利用多种移植瘤和转基因肝癌动物模型，研究Apelin与shRNA-MPHOSPH1/PRC1等细胞分裂抑制剂联合抗肝癌的分子机制，为发现药物新靶点、探索协同抗癌新策略提供思路。

由于恶性肝癌对化疗药物不敏感，因此发现肝癌治疗新靶点并探索有效的抗癌新策略十分迫切。我们在本项目中发现，在临床样本中脂肪因子Apelin在肝癌组织中表达下调，同时Apelin能通过促进肝癌血管正常化生长，提高CA4和紫杉醇等有丝分裂抑制类药物的抗癌效果并产生协同抗癌作用，是一个潜在的肝癌治疗新靶点。除此以外，我们还发现了MPHOSPH1和PRC1两个驱动蛋白调控肝癌细胞有丝分裂，抑制MPHOSPH1和PRC1能够协同促进靶向Apelin的抗肝癌治疗效果。同时利用各种动物模型，我们也研究了Apelin与shRNA-MPHOSPH1/PRC1等细胞分裂抑制剂联合抗肝癌的分子新机制，为发现药物新靶点、探索协同抗癌新策略提供了新的思路。