稀土氯化镧逆转卵巢癌顺铂耐药及机制研究

Ovarian cancer is a common female genital system malignant tumor type with the highest mortality rate. one of the reasons is cisplatin resistance. The main mechanism of cisplatin resistance is DNA repair gene ERCC1-mediated nucleotide excision repair. Nuclear transcription factor-kB (NF-kB) is a universal factor of regulation, including ERCC1, of cancer initiation, progress and metastasis. The prophase research has already confirmed, lanthanum chloride inhibit tumor cell proliferation, metastasis by the NF-kB signaling pathway, and also can enhance the toxic effects of cisplatin on ovarian carcinoma cells cultured in vitro . Based on the above knowledge and prophase research, we hypothesized that lanthanum chloride is most likely to down-regulated ERCC1 activation and expression by inhibiting NF-kB signaling pathway, weaken its DNA repair function in order to enhance the toxicity of cisplatin and to achieve reversal of its resistance. Therefore, first we screened the concentration of lanthanum chloride which had no biological effects on ovarian carcinoma cells the combination effect of lanthanum chloride and cisplatin in vitro and vivo will be observed to prove if it can reverse cisplatin resistance and also to investigate the mechanism of NF-kB pathway in regulation of ERCC1-mediated resistance. We hope to provide new ideas and ways to treat cisplatin-resistant ovarian cancer, and provide a scientific basis of development of rare earth medicinal value.

卵巢癌死亡率居妇科恶性肿瘤之首，原因之一是以铂类为基础的化疗耐药。DNA修复基因ERCC1介导的核苷酸切除修复为顺铂耐药主要机制。核转录因子-kB（NF-kB）是调控包括ERCC1在内的癌症起始、进展和转移的通用因子。我们前期研究证实，稀土氯化镧能够通过NF-kB信号通路抑制肿瘤细胞增殖、转移，同时能增强顺铂对体外培养卵巢癌细胞的毒性作用。基于以上认识和研究基础，我们推测：氯化镧极有可能通过抑制NF-kB信号通路来降调ERCC1的活化和表达，减弱其DNA修复功能从而增强顺铂毒性并实现逆转其耐药。为此，本课题首先筛选出对卵巢癌细胞及耐药株生物效应无明显抑制的氯化镧浓度；然后将其与顺铂联合作用于体外培养的卵巢癌耐药细胞株和体内移植瘤模型上，观察其能否逆转顺铂耐药并探讨NF-kB通路调控ERCC1介导的耐药机制，为顺铂耐药性卵巢癌的临床治疗提供新的思路和手段，并为开发稀土的药用价值提供科学依据。

卵巢癌死亡率居妇科恶性肿瘤之首，其主要原因是以铂类为基础的化疗耐药。肿瘤细胞的化疗耐药机制复杂，涉及众多的分子事件，氯化镧逆转卵巢癌顺铂耐药的机制也应是一个复杂的过程。本项目围绕氯化镧逆转卵巢癌顺铂耐药的研究方向，从体内、体外等方面展开了系列研究，取得的创新性成果包括：1.筛选出1.5umol/L浓度的氯化镧对卵巢癌细胞敏感株COC1及耐药株COC1/DDP无明显急性、慢性抑制作用，且与顺铂共培养，可以增强顺铂对COC1和COC1/DDP的抑制增殖作用及促进凋亡作用。2.成功建立耐药型卵巢癌动物模型，体内实验进一步验证，氯化镧与顺铂联合可以有效抑制卵巢癌耐顺铂实体瘤的生长，且组织中与增殖及肿瘤发生相关的蛋白表达下调，抑癌基因表达上调。3. 本项目通过差异蛋白质组学研究从整体角度分析细胞内动态变化的蛋白质组成成分、表达水平及修饰状态，发现了很多差异蛋白，下一步拟选取代表性蛋白作进一步研究，更深层次阐明氯化镧逆转卵巢癌顺铂耐药的分子机制及其可能的信号通路。项目资助发表SCI论文2篇，中文核心论文2篇。培养硕士生3名，其中2名已经取得硕士学位，1名在读。该项目通过四年的研究，圆满地完成了预定的科学目标，并为今后更深层次探究氯化镧逆转卵巢癌顺铂耐药的分子机制提供实验基础，为氯化镧的临床药用价值提供更科学、合理、安全的理论依据，为卵巢癌顺铂耐药患者提供新的治疗思路和理论依据。