TTP抑制IL6效应STAT3信号通路的活化及胰腺炎癌转化中的作用和机制研究

IL-6 plays a key role in the transformation of pancreatitis to cancer. IL-6/STAT3 is the effect downstream signaling pathway of IL-6, and great attention has been paid to its regulation mechanism. We found that the expression of TTP was significantly downregulated in pancreatic cancer tissues, which was closely related to the clinical stage of the corresponding patients. The results have been published on the journal of Oncotarget. However, the exact role of TTP in the pancreatitis’ transformation to cancer remains unknown. Accordingly, we constructed pancreatic epithelial cell specific TTP knock-out mice and pancreatitis’ transformation to cancer model by using the orthotopic pancreatic DMBA embeding. We found that the transformation to cancer was significantly increased in pancreatic epithelial cell specific TTP knock-out mice and the IL-6 effect and the STAT3 signal pathway activation was significantly enhanced, suggesting that TTP can inhibit the activation of IL-6 effect signal pathway to inhibit pancreatic inflammatory transformation to cancer. Accordingly, this project aims to study the relationship of the TTP expression in pancreatic cancer clinical specimens and the activation of STAT3 signaling pathway, and the function of TTP in pancreatic cancer cells and animal models. We also wound like to investigate the effect of TTP in the regulation STAT3 signaling pathway and the therapeutic effect of TTP inhibitor S3I-201 in the treatment of pancreatic cancer, in order to reveal the new mechanism of transformation of pancreatitis cancer, and novel potential targets in the treatment of pancreatic cancer.

IL-6在胰腺炎癌转化中发挥关键作用。IL-6 效应信号通路IL-6/STAT3活化的分子调控机制受广泛关注。申请人前期发现TTP在胰腺癌组织中表达显著下调，并与临床分期密切相关，以通讯作者发表于Oncotarget。但TTP在胰腺炎癌转化过程中的作用目前未知。据此，我们构建了胰腺上皮细胞特异性TTP基因敲除小鼠，并在胰腺原位包埋DMBA诱导的胰腺炎癌转化小鼠疾病模型中，发现胰腺上皮细胞TTP敲除小鼠胰腺炎癌转化显著增加，并且IL-6效应STAT3信号通路的活化显著增强，提示TTP能够通过抑制IL-6效应信号通路的活化进而抑制胰腺炎癌转化。据此，本项目拟研究胰腺癌临床标本TTP表达与STAT3信号通路活性关系；胰腺癌细胞模型和动物模型中TTP的功能； TTP对Stat3信号的调控及其抑制剂S3I-201对胰腺癌的治疗作用等。以期揭示胰腺炎癌转化新机制，为胰腺癌治疗和干预提出新的潜在靶点。

IL-6在胰腺炎癌转化中发挥关键作用，IL-6效应信号通路IL-6/STAT3活化的分子调控机制受广泛关注。我们发现TTP在胰腺癌组织中表达显著下调，并与临床分期密切相关,但TTP在胰腺炎癌转化过程中的作用目前未知。结合前期研究基础，我们揭示了临床标本中TTP表达与IL-6通路活性的相关性，构建了胰腺原位包埋DMBA诱导的胰腺炎癌转化小鼠模型，验证了TTP对正常胰腺细胞恶性转化的抑制作用，构建了胰腺类器官用于后续炎癌通路研究，检验了炎症因子IL-6对胰腺癌类器官的生长增殖及干性的影响。本项目相关研究结果将揭示胰腺癌TTP表达与STAT3信号通路活性关系；胰腺癌细胞模型和动物模型中TTP的功能以及TTP对Stat3信号的调控及其抑制剂S3I-201对胰腺癌的治疗作用等。明确胰腺炎癌转化新机制，为胰腺癌治疗和干预提出新的潜在靶点。