基于PDTX模型——胰腺癌化疗耐药相关的miRNAs筛选及其分子机制研究

Chemotherapy resistance is the important factors influencing the prognosis of cancer, the molecular mechanism of chemotherapy resistance in pancreatic cancer is still unclear. Studies show that miRNAs, EMT, CSCs can regulate the chemotherapy resistance of tumors, and the mechanism are closely related. Related research has not yet been reported in pancreatic cancer. Based on our previous research results, we speculate that miRNAs affect the pancreatic cancer chemotherapy resistance by adjusting CSCs and EMT. This program plan to detect the patient-derived tumor xenograft for high-throughput sequencing, using bioinformatics to filter the core miRNAs which regulate pancreatic cancer chemotherapy resistance and to bulid the miRNA-target gene networks. To reveal the mechanism of miRNAs regulating CSCs, EMT and chemotherapy resistance in vivo and in vitro. Evaluate the potential value of miRNAs as a treatment target in pancreatic cancer. Similar study has not been reported in domestic and foreign literature.

化疗耐药是影响肿瘤预后的重要因素，目前胰腺癌化疗耐药的分子机制尚不明确。研究表明miRNAs、肿瘤干细胞（CSCs）、上皮间质转化（EMT）对化疗耐药的调控作用既相互独立又密切相关，但它们之间的相互作用及分子机制在胰腺癌中尚未见报道。我们基于前期研究结果，推测“miRNAs-CSCs-EMT-化疗耐药”构成了一个复杂分子网络，耐药相关miRNAs可能通过调节CSCs特性、EMT表型影响了胰腺癌化疗耐药。本课题拟对人源胰腺癌小鼠移植瘤模型（PDTX）进行高通量测序，利用生物信息学筛选出调控胰腺癌化疗耐药的核心miRNAs，并构建耐药miRNAs-靶基因网络。在体内、体外水平探讨miRNAs对CSCs特性，EMT表型及化疗耐药的调控作用及其分子机制，并通过动物实验，探讨miRNAs作为胰腺癌治疗靶点的潜在价值。经检索，国内外文献尚未见类似研究报告。

胰腺癌是高度恶性的消化系统肿瘤，5年生存率不足8%，其中化疗耐药是导致胰腺癌患者预后差的主要原因之一。目前胰腺癌化疗耐药的分子机制尚不明确。本课题对人源胰腺癌小鼠移植瘤模型（PDX）进行高通量测序，利用生物信息学筛选出调控胰腺癌化疗耐药的核心miRNAs。发现了胰腺癌PDXs模型可以有效的代表亲代胰腺癌的组织学和分子特征;完成了吉西他滨在PD X模型中的药效学实验，PDXs模型可作为吉西他滨治疗反应的预测模型和预测患者预后的标志物；验证了既往的胰腺癌亚型分类难以忠实的反映胰腺癌的化疗敏感性；探索了胰腺癌吉西他滨内源性耐药的分子特征，构建了胰腺癌耐药相关的miRNAs-mRNA调控网络;筛选出了调控胰腺癌化疗耐药的核心mRNA与miRNAs，发现miRNA-135a可作为判断胰腺癌患者吉西他滨疗效和预后的生物标志物;发现了miR-135a可以促进胰腺癌的化疗耐药、迁移和增殖，miR-135a通过下调β-TrCP抑制了EMT信号通路，从而促进了胰腺癌的发生发展。MiR-135a有望成为治疗胰腺癌的新靶点。