Dissecting the function of c-Rel in pancreatic cancer and its therapeutic implications

核因子-κB信号通路是炎症和癌症的媒人。有许多研究表明它在胰腺癌中的重要性，重点放在上游调节该途径的激酶和受体上。虽然这些蛋白在功能上对NF-κB功能非常重要，但它们在其他信号通路中也具有多效性影响。为了绕过这样的问题，一种方法是更多地关注下游转录因子，以用于基础科学研究和治疗开发。我们之前的研究已经显示了单独的NF-κB转录因子RelA和RelB如何以及为什么在胰腺癌的发生和持续性中起重要作用。到目前为止，c-Rel已被分析用于血液系统恶性肿瘤。与RelA和RelB不同的是，关于c-rel在实体瘤中的作用的研究有限。我们认为，缺乏这些研究并不是因为c-rel在这些实体中的功能微不足道，而是无意识地忽视了这一点。因此，在目前的提案中，我们总结了许多先前关于c-rel在实体瘤中的作用的研究。重要的是，我们提供了c-rel在胰腺癌中值得注意的功能的数据。特别是，我们提供了在基础研究中探索c-rel功能的初步证据，为开发治疗方案铺平了道路。通过使用不同的胰腺癌小鼠模型，我们提供了REL基因过表达如何降低总体生存率的证据。基于我们的小鼠移植实验，我们还获得了c-rel过度表达上调转移的证据。通过使用更多的小鼠模型，我们的目标是阐明c-rel功能在原发肿瘤发生和转移中的重要性。其中，REL条件性基因敲除小鼠模型将具有特别重要的意义，我们已经开始培育该模型。同时，我们的目标是进行体内和体外实验，从功能和分子上分析c-rel的影响。因此，我们已经建立了一个由多个小组组成的合作网络，这些小组都是各自领域的专家。总体而言，在这项建议中，我们提供了工作计划，其中我们将描绘以下假设：NF-κB转录因子c-Rel调节胰腺癌的严重程度和转移潜力。最终，通过使用以前发表的c-rel抑制剂，我们的目标是开发降低原发肿瘤严重程度和转移负担的策略。

NF-κB signaling pathway is the matchmaker of inflammation and cancer. There are many studies signifying its importance in pancreatic cancer, with a focus on the kinases and receptors regulating the pathway at the upstream. Although these proteins are functionally very important for NF-κB function, they have pleiotropic impact in other signaling pathways. In order to bypass such a problem, an approach is to rather focus on downstream transcription factors for both basic science percipience and therapeutic exploitation. Our previous research already showed how and why the individual NF-κB transcription factors RelA and RelB are important in pancreatic carcinogenesis and persistency. c-Rel has so far been analyzed in hematological malignancies. Unlike RelA and RelB, there are only limited amount of studies regarding c-Rel function in solid tumors. We believe that lack of these studies is not due to the insignificant function of c-Rel in these entities but rather an unconscious overlook. Therefore in the present proposal, we summarized many previous studies signifying the role of c-Rel in solid tumors. Importantly, we offer data portending the noteworthy function of c-Rel in pancreatic cancer. Particularly, we provide preliminary evidence how exploration of c-Rel function in basic research would pave a way for the exploitation of therapeutic options.With the use of different pancreatic cancer mouse models, we provide evidence how Rel genetic overexpression reduced overall survival. Based on our mouse transplantation experiments, we also procure evidence that overexpression of c-Rel upregulated metastasis. With the use of additional mouse models, we aim to elaborate the importance of c-Rel function in primary tumor carcinogenesis and metastasis. Among these, the Rel conditional knock-out mouse model will be of special importance which we already started to breed. In parallel, we aim to perform both in vivo and in vitro experiments analyzing c-Rel impact both functionally and molecularly. Accordingly, we already generated a collaboration network with multiple groups which are all experts in their respective fields.Overall, within this proposal we provide the work programme in which we will delineate the following hypothesis “NF-κB transcription factor c-Rel regulates the severity and metastatic potential of pancreatic cancer”. Eventually, with the use of previously published c-Rel inhibitors, we aim to develop strategies reducing both primary tumor severity and metastatic burden.