Functional characterization of Bcl-3 in pancreatic cancer

胰腺导管腺癌(PDAC)仍然是预后最差的肿瘤之一。除了早期转移外，对放化疗的强烈抵抗力也是该病死亡率仍然很高的原因。因此，识别新的与治疗相关的信号通路是当前研究活动的重点。与其他研究小组一起，我们确定JAK2/STAT3信号通路是治疗胰腺癌的相关靶点。在第一个资助期的帮助下，我们利用不同的遗传模型研究了STAT3的激活机制。我们进一步观察到STAT3的激活对非典型蛋白IkappaB的表达的干扰。这种蛋白与胰腺癌发生的相关性还没有研究过。在初步工作中，我们能够证明，不仅在大多数人类癌细胞系中可以检测到Bcl-3，而且在胰腺标本中也可以检测到。它在小鼠模型中的遗传失活揭示了其抑制肿瘤的作用。Bcl3基因缺失可导致胰腺癌的显著转移。因此，这项建议的重点是确切地调查Bcl-3和STAT3之间的干扰及其相关性。我们还将描述作为肿瘤抑制因子的Bcl3的功能。从长远来看，我们希望这个项目加深我们对Bcl3/STAT3轴在胰腺癌病理生理和治疗中的作用的理解。

Pancreatic ductal adenocarcinoma (PDAC) remains one of the tumors with the worst prognosis. In addition to early metastasis strong resistance toward radiation and chemotherapy account for the still very high mortality of this disease. Identification of new therapeutically relevant signaling pathways is therefore among others the focus of current research activities. Together with other research groups we identified the Jak2 / Stat3 signaling pathway as a relevant target in the treatment of pancreatic cancer. With the help of the first funding period we worked up the mechanisms of peristenten Stat3 activation using various genetic models. We furhter observed an interference of Stat3 activation with the expression of Bcl-3, an atypical protein IkappaB. The relevance of this protein for pancreatic carcinogenesis has not been studied. In preliminary work we were able to demonstrate that Bcl-3 is detectable not only in most human cancer cell lines, but also in pancreatic specimens. Its genetic inactivation in murine mouse model reveals a tumorsuppressive role. Deletion of Bcl-3 leads to a pronounced metastasis of pancreatic cancer. The focus of this proposal is therefore the exact investigation of interference between Bcl-3 and Stat3 and its relevance. We will also characterize the function of Bcl-3 as a tumorsuppressor. In the long term, we hope this project deepens our understanding og the role of the Bcl-3/Stat3 axis in the pathophysiology and treatment of pancreatic cancer.