胰腺癌化疗效果不佳，预后极差，化疗耐药为根本性原因。本课题组前期研究发现： Hedgehog（Hh）信号通路介导BRG1参与调控胰腺癌细胞获得性化疗耐药，抑制Hh活性后BRG1显著上调，且BRG1的异常表达导致与肿瘤干细胞相关的miRNA转录水平改变，但其调控机制仍不明确。本课题拟通过调控Hh信号通路活性，观察BRG1表达变化及其对胰腺癌细胞化疗药物敏感性的影响，并在耐药株中进行验证；通过改变BRG1表达水平，证明Hh-BRG1途径对胰腺癌肿瘤干细胞及化疗药物敏感性的调控作用；在不同BRG1表达水平的胰腺癌细胞系中，对前期工作中筛选出的与肿瘤干细胞相关的miRNA进一步检测及功能性验证，以明确miRNA对上述变化有调控作用；建立动物模型，体内条件下进一步验证Hh-BRG1及miRNA介导肿瘤细胞干细胞化并产生化疗耐药，探寻改变胰腺癌细胞耐药行为的治疗靶点。

The prognosis of pancreatic cancer is very poor because of its resistance to chemotherapy. Our previous study showed that BRG1 modulated by Hedgehog (Hh) signaling pathway regulated the acquired chemoresistance in pancreatic cancer cells. Inhibition of Hh signaling pathway led to a significant up-regulation of BRG1 expression. Moreover, the abnormal expression of BRG1 resulted in the significant changes of cancer stem cell related miRNAs transcription. The mechanisms of these regulations are not clear. In this study, the activity of Hh pathway will be changed to find out the modulation of BRG1 expression and chemosensitivity in pancreatic cancer cells, as well as in chemoresistant strains. The expression level of BRG1 will be increased and suppressed by expressional vector and siRNA technology respectively, and the corresponding changes of cancer stem cell transformation and chemoresistance will be studied in order to show the role of Hh-BRG1 in these processes. In pancreatic cancer cell lines with different BRG1 expression levels, the altered miRNA transcription patterns will be screened in order to find out the crucial role of miRNAs on the Hh-BRG1 modulated cancer stem cell transformation and acquired chemoresistance in pancreatic cancer cells. Finally, studies in vivo will be proposed to validate these regulatory mechanisms, and to find out a more effective method which contributes to enhancing the chemosensitivity of pancreatic cancer cells.