EZH2表观调控胰腺肿瘤干细胞耐药性的作用机制及分子靶向治疗的研究

PCSCs possesses the capacity of both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of pancreatic cancer. EZH2 is a crucial factor playing a role in the maintenance of self-renewal of adult and embryonic stem cells，while EZH2 expression is reduced in differentiated cells. Since EZH2 overexpression is linked to cancer initiation and metastasis and considering that high-grade tumors are enriched with a high content of PCSCs, it is proposed that EZH2 expression could favor the transition of dormant progenitors and/or differentiated cells into a more aggressive stem-cell like phenotype. However, the molecular mechanisms involved in EZH2 dysregulation in cancer appear to be diverse. Here, we correlated EZH2 with H3K27me3 levels in pancreatic cancer and evaluated response to gemcitabine in pancreatic cancer stem cells. With genetically engineered mouse models, Patient-derived tumour xenografts and human pancreatic ductal adenocarcinoma cell lines, we will further investigate the mechanisms of EZH2 dysregulation in cancer and progresses in therapeutic approaches targeting EZH2. The prospective results of this project will not only help to explore the role and mechanistic basis of the oncogenic role of EZH2 but also to provide insights on novel therapeutic strategies against pancreatic cancer.

胰腺癌干细胞(PCSCs)的分化潜能是胰腺癌细胞异质性的基础，其自我更新、无限增殖能力与胰腺癌的发生、复发转移及对化疗耐受能力密切相关。EZH2及其介导的H3K27me3不仅是维持胚胎干细胞多能性的关键因素，而且对PCSCs的表观可塑性也具有关键的调控作用。初步结果发现，EZH2与胰腺癌细胞系吉西他滨耐药性正相关且在胰腺肿瘤干细胞中升高表达。基于此，本课题做出了如下假设：在化疗药物处理时，胰腺癌细胞通过上调EZH2及其介导的H3K27me3表观修饰抑制基因转录，维持肿瘤细胞的干细胞特性而增加耐药性。本项目拟借助永生化的胰腺细胞株、病人来源的肿瘤干细胞以及胰腺细胞中条件性敲除EZH2的KPC基因工程小鼠，从体外、体内、活体水平深入探索EZH2如何调控肿瘤干细胞的多分化潜能及化疗耐药。本项目不仅能够提高对胰腺癌化疗耐药的表观调控机制的认识，也将为发现新的药物治疗靶点及其诊断标志物提供实验基础。

胰腺癌干细胞(PCSCs)的分化潜能是肿瘤细胞异质性的基础，其自我更新、无限增殖能力与胰腺癌的发生、复发转移及对化疗耐受能力密切相关。EZH2及其介导的H3K27me3不仅是维持胚胎干细胞多能性的关键因素，而且对PCSCs的表观可塑性也具有关键的调控作用。研究发现，EZH2与人源胰腺癌细胞系吉西他滨耐药性正相关且在胰腺肿瘤干细胞中升高表达。本研究借助永生化的胰腺细胞株从细胞层面开始深入探索EZH2如何调控肿瘤干细胞的多分化潜能及化疗耐药。EZH2在体外能促进癌症细胞的增殖和转移。EZH2的小分子抑制剂，UNC1999，和HDAC抑制剂panobinostat联用，可以降低两种药物的IC50，两种药物可在体外发挥协同作用抑制胰腺癌发生发展。研究发现与对照相比EZH2敲减细胞系中CD24在mRNA水平表达下降，Western Blotting中CD133与CD44表达下降，说明EZH2会影响肿瘤的干性能力。肿瘤干细胞是癌症产生耐药的重要原因之一，EZH2对肿瘤细胞的干性起到了维持作用，有望成为新的治疗靶点。