miR-301a调控NFκB/Stat3介导的非可控性胰腺炎恶性转化机制与靶向性治疗研究

NF-κB/Stat3 signaling pathway plays a key role in nonresolving inflammation-promoting tumorigenesis and tumor development. miR-301a has been proved to be highly expressed in PDAC and activate NF-κB/Stat3 pathway. Our previous study showed target deletion of miR-301a can inhibit pancratitits and pancreatitis-induced pancreatic intraepithelial neoplasia (PanIN) formation, which indicated that miR-301a may be involved in the process of nonresolving inflammation promoting pancreatic tumorigenesis. In the current project, miR-301a knockout mice and KrasG12D;Pdx1-Cre transgenic mice were used to further study: 1) the mechanisms of miR-301a in Caerulein accerlerating Kras-induced PanIN and PDAC formation; 2) synthesis, characterization, and evaluation of poly (D,L-lactide-co-glycolide)(PLGA)-based nanoformulation of anti-miR-301a on PanIN formation; 3) whether the expression of miR-301a and its targets are correlated with the clinicopahtologic parameters in clinic pancratic ductal adenocarcinoma samples. Thus, the proposed studies will emphasize targeting miR-301a regulating NF-κB/Stat3 signaling pathway involved inflammation- promoting tumor growth as a new therapeutic avenue to tumor growth and development. And the study will explore the role of miR-301a inhibitor in inflammation-promoting tumor growth and also emphasize to find the new target for clinical treatment of pancratic ductal adenocarcinoma.

NF-κB/Stat3信号通路在非可控性炎症恶性转化进程中起着非常重要的作用。miR-301a在胰腺癌（PDAC）中表达升高并可同时激活NF-κB/Stat3炎症信号通路，我们前期的研究表明靶向敲除miR-301a可以抑制NF-κB/Stat3炎症信号，并降低胰腺上皮内瘤样变（PanIN）病理进程，结果提示我们miR-301a参与非可控性胰腺炎恶性转化进程。本项目进一步研究：1) miR-301a在雨蛙素诱发胰腺癌基因工程小鼠PanIN和PDAC进程中的分子机制；2) 以PLGA纳米粒包裹miR-301a抑制剂对PanIN形成的靶向性抑制作用；3) 采用临床PDAC样本研究miR-301a表达差异与PDAC病理特征关系。本研究期望以miR-301a调控NF-κB/Stat3信号通路为靶向，探索miR-301a抑制剂抑制非可控性炎症恶性转化的新方法，为胰腺癌的临床治疗提供新思路。

本项目以miR-301a基因敲除小鼠为主要研究对象，建立了小鼠急性、慢性和胰腺癌前病变（PanIN）模型，完成的研究目标包括：基因敲除miR-301a不能有效的降低雨蛙素诱导的小鼠急性胰腺炎的发生和发展，但是可以显著性降低雨蛙素诱导的小鼠慢性胰腺炎的发生和发展以及雨蛙素诱导的、及小鼠自发产生的PanIN胰腺损伤；研究揭示了miR-301a介导的这一炎症及炎症诱导上皮细胞恶性转化的机制，提出miR-301a是PanIN干预治疗的新靶点；研究发现了miR-301a调控PanIN发生和发展的新信号通路：TGF-β/TSC1/mTOR，miR-301a通过这一信号通路调节胰腺PanIN成纤维细胞和星状细胞介导了PanIN的形成；研究采用第二种纤维化模型，即肺组织纤维化来证实miR-301a在纤维化中的作用机制，实验采用博来霉素诱导小鼠肺纤维化模型，使用miR-301a的抑制剂可以有效的抑制小鼠肺组织的纤维化进程；实验为进一步在临床采用microRNA的抑制剂治疗脏器的纤维化和癌前病变提供了新的靶标及其新的研究思路。