Interaction between transcription factors RelA and Stat3 in pancreatic carcinogenesis

胰腺导管腺癌（PDAC）是一种长期预后不佳的高致死率疾病。由于缺乏临床症状，诊断晚，治疗难治，PDAC是全球癌症相关死亡的八大原因之一，也是任何类型胃肠道疾病死亡的第二大常见原因。尽管在手术、化疗和放疗方面取得了长足的进步，但PDAC的预后仍然非常差。NF-kB家族蛋白和Stat3作为最普遍表达的转录因子，可以通过调控大量下游基因的表达来控制包括胰腺癌在内的许多实体肿瘤的生长和恶性，这些下游基因控制细胞增殖、存活、应激和免疫反应。其中一些基因重叠，需要两个因子之间的转录合作。近年来的研究表明，Stat3与NF-kB的相互作用在肿瘤发生和免疫系统反应的控制中起着重要作用。虽然NF-kB和Stat3信号在胰腺癌中的激活已被证实，但NF-kB亚基RelA和PDAC中Stat3之间的相互作用尚未完全了解。因此，我们计划确定RelA和Stat3运作的分子机制，并确定如何将这些知识用于未来的药物开发和临床应用。

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal long-term prognosis. Due to the paucity of clinical signs late diagnosis and refractory nature toward treatment, PDAC is one of the eight-leading causes of cancer-related death worldwide and is the second most common cause of death from any type of gastrointestinal disease. In spite of profound advances in surgery, chemo-, and radiation therapy, the prognosis of PDAC remains extremely poor.As mostly ubiquitously expressed transcription factors, proteins of the NF-kB family and Stat3 can control the growth and malignancy of many solid tumors, including pancreatic cancer, via the regulation of expression of a large number of downstream genes that control cell proliferation, survival, stress and immune responses. Some of these genes overlap and require transcriptional cooperation between the two factors. Recent studies have revealed that interaction between Stat3 and NF-kB plays an important role in carcinogenesis and in control of response of the immune system. Although the activation of NF-kB and Stat3 signaling in pancreatic cancer has been shown, the interaction between the NF-kB subunit RelA and Stat3 in PDAC is not completely understood. Thus, we plan to define the molecular mechanisms through which RelA and Stat3 operate and to determine how this knowledge could be exploited for future drug development and clinical applications.