慢性胰腺炎是胰腺癌发生、发展的高危因素。文献报道，IL-6与Notch相互作用，调节上皮细胞增殖及肿瘤干细胞的发生，二者是否参与慢性胰腺炎恶性转化目前尚不清楚。我们前期发现IL-6在慢性胰腺炎及胰腺癌患者血清中表达水平较健康人显著升高，提示IL-6可能是慢性胰腺炎恶性转化的血清标志物之一，但作用及机制尚不明确。本课题拟通过在体实验（雨蛙肽腹腔注射自发胰腺癌变转基因K-rasG12D小鼠建立慢性胰腺炎恶性转化模型）和离体实验（原代培养K-rasG12D小鼠胰腺导管上皮细胞），动态监测IL-6、STAT3、Notch家族成员表达水平及胰腺组织病理变化，探讨IL-6/STAT3/Notch信号通路在慢性胰腺炎（CP）向胰腺上皮内瘤变（PanIN）、胰腺癌（PDAC）转化过程中的作用及机制。以期通过本课题为阐明慢性胰腺炎恶性转化机制、胰腺癌早期预防、临床诊断及治疗靶点提供理论依据。

Chronic pancreatitis is one of the high-risk factors for incidence of pancreatic cancer. Inflammation mediated by IL-6 play a vital role in chronic pancreatitis. Previous researches indicated that cross-talk between IL-6 and Notch involved in regulation the epithelial cell prolifferation、epithelial-mesenchymal transition and cancer stem cell generation. There may be exist the synergism between IL-6 and Notch signaling pathwayes. In our previous study, we found that the serum level of IL-6 increased significantly in chronic pancreatitis and pancreatic cancer patients , that indicated that IL-6 maybe the potential biomarker of pancreatic malignant transformation. In this study, by means of pancreatic ductal epithelial cell primary culture technology (in vitro) and gene engineer mouse K-rasG12D (in vivo), chronic pancreatitis was induced by intraperitoneal injection of Caerulein. We will explore the mechanisms of IL-6 signal pathway and Notch signaling in the progresses among chronic pancreatitis (CP), pancreatic intraepithelial neoplasia (PanIN) and pancreatic carcinoma (PDAC). Based on our current study, we will clarify the mechanisms of IL-6/STAT3/Notch in PDAC process. We hope to find out the beneficial clinical diagnosis and more effective follow-up indicators, which will promote pancreatic cancer early detection and target therapy.

流行病学研究及动物模型研究表明，慢性炎症状态是胰腺癌发生、发展的高危因素。长期的炎症反应引起胰腺实质腺泡渐进损失，进一步加剧了慢性炎症反应，形成了炎症的级联放大效应，并最终引起细胞凋亡抑制及异常增殖，形成胰腺上皮内瘤变（Pan IN）及胰腺癌变。我们当前的研究表明，IL-6通过调节Notch通路活性及Notch-1/MYH-9相互作用，调节胰腺癌细胞增殖、迁移及浸润。结果表明，一定剂量的IL-6对胰腺癌细胞增殖具有显著的促进作用，但阻断Notch-1通路，显著减弱了IL-6的作用；细胞划痕及细胞浸润实验结果表明IL-6通过调节Notch-1信号通路促进胰腺癌细胞的迁移；细胞免疫共沉淀结果表明，Notch-MYH-9相互作用可能在IL-6调节胰腺癌细胞迁移中发挥重要作用，具体机制需要进一步深入探讨。当前的研究为进一步探讨IL-6/Notch-1/MYH-9通路在慢性胰腺炎向胰腺癌恶性转化中的作用奠定了基础。