磷脂酶D1(PLD1)介导胰腺癌吉西他滨耐药的分子机制及逆转策略

耐药是导致胰腺癌治疗失败的重要原因。为挖掘胰腺癌潜在的耐药机制，前期课题组成功构建胰腺癌基因组过表达文库细胞，利用生物信息学分析筛选出吉西他滨耐药相关基因—磷脂酶D1(PLD1)。预实验显示PLD1在胰腺癌组织及耐药细胞株中呈现高表达，外源性过表达PLD1及其酶活性可显著影响胰腺癌细胞对药物的敏感性。同时发现PLD1所介导的耐药与其异常的核定位有关。通过转录组测序，初步确定NLRP1为PLD1的下游作用靶点，通过抑制细胞凋亡发挥介导耐药的作用，但其内在具体机制尚未明确。故本课题拟以前期工作为基础，从临床样本、细胞和动物实验中进一步明确PLD1在胰腺癌耐药表型中的作用、PLD1-NLRP1-凋亡调控轴介导耐药的内在机制以及靶向PLD1逆转耐药的治疗策略，力图为改善胰腺癌的耐药现象提供新的理论思路。

Drug resistance is an important cause of treatment failure in pancreatic cancer. In order to explore the potential drug resistance mechanism of pancreatic cancer, our group successfully constructed pancreatic cancer genomic overexpression library and screened the gemcitabine-resistance-related gene-phospholipase D1 (PLD1), by using bioinformatics analysis. Preliminary experiments showed that PLD1 was highly expressed in pancreatic cancer tissues and drug-resistant cell lines, and overexpression of PLD1 and its enzymatic activity could significantly affect the sensitivity of pancreatic cancer cells to the drug. The drug resistance mediated by PLD1 was also found to be associated with its abnormal nuclear localization. NLRP1 was initially identified as the downstream target of PLD1 by transcriptome sequencing, which mediates drug resistance by inhibiting apoptosis. However, its specific mechanism remains unclear. Therefore, based on the previous work, we intend to further clarify the role of PLD1 in the drug-resistant phenotype of pancreatic cancer, PLD1-NLRP1-apoptosis axis in mediating drug resistance and the therapeutic strategy of reversing drug resistance by targeting PLD1 from clinical samples, cells and animal experiments. Finally we attempt to provide new theoretical ideas for improving the drug resistance in pancreatic cancer.