Interaction between transcription factors RelA and Stat3 in pancreatic carcinogenesis

胰腺导管腺癌（PDAC）是一种高致死性疾病，长期预后差。由于缺乏临床体征、晚期诊断和治疗难治性，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的第二大常见死亡原因。尽管在手术、化疗和放射治疗方面取得了巨大进展，但PDAC的预后仍然非常差，NF-kB家族和Stat 3蛋白作为大多数广泛表达的转录因子，可以通过调节大量控制细胞增殖、存活、应激和免疫反应的下游基因的表达来控制许多实体瘤（包括胰腺癌）的生长和恶性程度。其中一些基因重叠，需要两个因子之间的转录合作。最近的研究表明，Stat 3和NF-kB之间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。尽管已经显示了胰腺癌中NF-κ B和Stat 3信号传导的激活，但PDAC中NF-κ B亚基RelA和Stat 3之间的相互作用尚未完全了解。因此，我们计划确定RelA和Stat 3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.