外泌体源性lncRNA DDX6P调控胰腺癌灌注化疗耐药的功能和机制研究

Pancreatic cancer ranks fourth among cancer-related deaths, and the 5 years survival rate is less than 6%. Most patients missed the chance to receive operation. Arterial infusion is an efffetive method to treat locally progressive advanced pancreatic cancer, but drug-resistance is the leading cause for poor prognosis. Recent study showed that exosomes and lncRNA play a key role in pancreatic cancer drug-resistance regulating mechanism, and are the new direction for tumor drug-resistance study. Our study group previously found that lncRNA DDX6P derived from exosomes in pancreatic cancer culture highly expressed after gemcitabine drug-resistance assay, but decreased in parental cells. And showed that apoptosis was accelerated, and growth and invasion undermined. Results gathered prompt that lncRNA DDX6P may participate in the pancreatic cancer drug-resistance regulating mechanism. We intend to analyze how lncRNA DDX6P regulated pancreatic cancer drug-resistance regulating mechanism by molecular, cellular, in vivo and pathological level, which will give us a sight into the pancreatic cancer drug-resistance regulating mechanism and find the new potential marker for restoring pancreatic cancer drug-resistance. This proposal will provide a new direction for improving clinical effectiveness of pancreatic cancer chemotherapy.

胰腺癌是导致死亡的第四位恶性肿瘤，其5年生存率不足6%。多数患者在确诊时已丧失手术机会，胰腺癌动脉灌注化疗是治疗中晚期胰腺癌局部进展的有效治疗手段，但化疗耐药是导致预后差的主要原因。近期研究表明，外泌体及其lncRNA在调控胰腺癌细胞耐药机制中具有重要作用，是肿瘤耐药新的研究方向。课题组前期研究发现，胰腺癌细胞在进行吉西他滨耐药处理后，其培养基外泌体中lncRNA DDX6P显著下降，而在lncRNA DDX6P高表达的亲本代胰腺癌细胞株中，胰腺癌细胞凋亡加速，增殖和侵袭能力减弱。提示lncRNA DDX6P可能参与胰腺癌化疗耐药。本研究拟从基因、蛋白、体内及临床病理水平探讨lncRNA DDX6P调控胰腺癌化疗耐药的分子机制，深入分析胰腺癌耐药可能的作用机制，为寻找逆转胰腺癌耐药的潜在有效靶点、提高胰腺癌化疗的临床疗效提供新的治疗方向。

本研究旨在探讨GAS41在胰腺癌中的增殖、干细胞特性以及化学抗性作用的机制研究。本研究的计划主要分为4个方面：（1）探讨GAS41和H2A.Z.2在胰腺癌的作用；（2） 探讨GAS41对Notch的调控作用；（3）探讨GAS41对H2A.Z.2的调控作用；（4）明确GAS41 通过 H2A.Z.2 和 Notch1 在胰腺癌中介导增殖、干细胞特性和 GEM 化学抗性的作用机制。本研究已经基本按照原计划完成并得到相应的研究结果，旨在为胰腺癌的治疗提供一定的理论依据。通过实验验证，1) GAS41在人胰腺癌组织和细胞系中过表达；2) GAS41促进胰腺癌细胞的肿瘤发生、干细胞特性和GEM耐药性；3) GAS41 在体内促进胰腺癌肿瘤发生、干细胞特性和 GEM 耐药性；4) GAS41通过上调Notch通路促进肿瘤发生和GEM耐药；5) H2A.Z.2介导胰腺癌细胞的肿瘤发生、干细胞性和GEM耐药性；6) 乙酰化H2A.Z.2上调Notch；7) GAS41激活Notch及其下游因子；8) GAS41 与 H2A.Z.2 结合在体内促进胰腺癌肿瘤发生、干细胞特性和 GEM 抗性。该课题的研究成果为进一步理解胰腺癌的耐药性提供了新的证据，为人类攻克胰腺癌提供了更多可能性。