缺氧诱导因子-1（HIF-1）与Notch信号通路在胰腺癌变中相互调控机制及靶向抑制剂联合治疗的研究

胰腺癌是一种死亡率高、预后差的恶性肿瘤；传统化疗易产生耐药性且耐受性差。胰腺癌变中多条信号通路发生异常活化，为靶向药物联合治疗的提供了可能。缺氧诱导因子-1（HIF-1）和Notch信号通路均在胰腺癌变过程中异常活化，分别单独抑制可减缓胰腺癌变进程。本组预实验基于已建立的Kras突变小鼠胰腺癌变模型、以及临床胰腺癌患者肿瘤组织标本，发现两条通路同步活化；小鼠模型单独使用Notch抑制剂可同时部分抑制两条信号通路；提示两条信号通路活化存在相关性，且为潜在靶向联合治疗靶点。本研究拟进一步在小鼠胰腺癌变模型进行在体实验，利用靶向药物干预研究两条信号通路联合抑制对胰腺癌的联合抑制效果。进一步，通过胰腺癌细胞系分别对两条信号的关键分子进行敲低和过表达实验，明确其相互调控机制及关键调控分子，并为联合用药策略提供实验依据。

Pancreatic cancer is one of the most deadly malignancies with extremely poor prognosis. Drug resistance and patients’ intolerance to chemotherapeutics limited the effectiveness of current treatment. Multiple intracellular signaling pathways have been demonstrated to be abnormally activated during pancreatic tumorigenesis, thus making it possible to discover novel targeted inhibitors to treat this disease. It is known that hypoxia inducible factor-1 (HIF-1) and Notch signaling pathways were both hyper-activated during pancreatic tumorigenesis. Inhibitions of either HIF-1 or Notch pathway could decelerate pancreatic cancer progression. Our previous study found that HIF-1 and Notch pathways were simultaneously activated in both KrasG12D transgenic pancreatic cancer mouse model and human pancreatic cancer tissue samples. Pharmacological inhibition of Notch signaling in Kras mutant transgenic pancreatic cancer mouse not only suppressed Notch signaling activity, but also partially inhibited HIF-1 signaling activity. Based on that, HIF-1 and Notch pathways were activated at the same time during pancreatic tumorigenesis. It also provide potential therapeutic target for combined target therapy. This study aims to further evaluate the combination therapeutic effectiveness of both pathways’ inhibitors on Kras mutant transgenic pancreatic cancer mouse model. Furthermore, we also aim to study the molecular regulation mechanism and key regulatory molecules based on pancreatic cancer cell lines. In detail, the key molecules of HIF-1 and Notch pathways will be knocked down or over expressed, and the downstream molecules would be assayed. In conclusion, this study aims to providing experimental evidences for combined HIF-1 and Notch inhibition therapeutic strategy.