LSM4蛋白质参与DNA同源重组修复及卵巢癌铂类药物耐药机制的研究

Platinum resistance in ovarian cancer chemotherapy is the big challenge in clinical treatment. It`s known that deregulated DNA homologous recombination repair efficiency can promote ovarian cancer cell death caused by platinum drug. Our previous work found overexpression VEGF111b inhibits proliferation of the ovarian cancer cells though targeting VEGF-R2 and its signaling pathway. This opens a new avenue for treating ovarian cancer（J Transl Med. 2015). In order to find a new molecular target to combined cisplatin therapy, we analyzed cancer genome database (Oncomine) and a resource for whole genome screen for homologous recombination mediator. Finally, we found a novel DNA repair regulator-LSM4. Our preliminary data indicate LSM4 is highly expressed in ovarian cancer, and its expression can be up-regulated by IR stimulate. We also found knockdown LSM4 can lead DNA double strands break, and sensitized the ovarian cancer cells to cisplatin. Based on these important results, we will unravel the detailed function of LSM4 in DNA damage and repair procedure. This will pave the way to find new target for cancerous diagnose and develop a novel cisplatin combination strategy for ovarian cancer therapy.

卵巢癌化疗中铂类药物耐药是临床面临的重大难题，已知通过下调DNA同源重组修复效率可促进铂类药物诱发的卵巢癌细胞凋亡，增强化疗效果。我们前期工作发现过表达VEGF111b可靶向VEGF-R2和其信号通路，从而抑制卵巢癌的生长，为卵巢癌的靶向治疗提供了新的途径（J Transl Med. 2015)。近期为了找到可协同铂类药物治疗且参与同源重组调控的分子靶标，我们结合肿瘤基因组数据库（Oncomine）及全基因组筛选同源重组调控蛋白质文献综合分析，筛选得到一个新的DNA损伤修复调控子-LSM4。前期实验数据发现LSM4在卵巢癌中特异性高表达，IR照射可诱导其蛋白量上调，且干涉LSM4可导致DNA双链断裂并促进顺铂对卵巢癌细胞杀伤的敏感性。本项目拟在前期已取得重要线索基础上，通过深入阐明LSM4在DNA损伤修复中的调控模式，揭示其在临床卵巢癌早期诊断及联合铂类药物化疗中的意义。

卵巢癌化疗中铂类药物耐药是临床面临的重大难题，已知通过下调DNA同源重组修复效率可促进铂类药物诱发的卵巢癌细胞凋亡，增强化疗效果。我们前期工作发现过表达VEGF111b可靶向VEGF-R2和其信号通路，从而抑制卵巢癌的生长，为卵巢癌的靶向治疗提供了新的途径（J Transl Med. 2015)。近期为了找到可协同铂类药物治疗且参与同源重组调控的分子靶标，我们结合肿瘤基因组数据库（Oncomine）及全基因组筛选同源重组调控蛋白质文献综合分析，筛选得到一个新的DNA损伤修复调控子-LSM4。前期实验数据发现LSM4在卵巢癌中特异性高表达，IR照射可诱导其蛋白量上调，且干涉LSM4可导致DNA双链断裂并促进顺铂对卵巢癌细胞杀伤的敏感性。本项目拟在前期已取得重要线索基础上，通过深入阐明LSM4在DNA损伤修复中的调控模式，揭示其在卵巢癌癌前诊断及联合顺铂治疗中的临床意义。