探索自噬与肿瘤的关系是生命科学领域研究热点之一。申请人的研究表明HMGB1是一种新型的自噬调节蛋白，并且可能是一种重要的胰腺癌抑癌蛋白。在此研究基础之上，申请者提出“HMGB1依赖性自噬通路通过拮抗内源性（基因组不稳定性）和外源性（炎症反应）促癌通路，从而抑制胰腺癌形成”的科学假说。针对上述假说，本项目拟选用转基因动物和胰腺癌细胞为主要研究材料，采用RNA干扰、免疫共沉淀、免疫组化、免疫荧光和电镜等研究手段，在整体、细胞和分子水平，进一步深入系统的探讨HMGB1依赖性自噬通路调节胰腺癌的分子机制、探索干预HMGB1依赖性自噬通路防止胰腺癌发生的手段。开展本项目可望揭示HMGB1在肿瘤的作用机制，为自噬的研究开辟新的领域，为寻找胰腺癌治疗药物和检测手段提供新的思路与实验线索，具有重要的科学意义和潜在的应用前景。

Pancreatic cancer, one of the most lethal cancers worldwide, has a unique relationship with autophagy. However, the molecular mechanisms linking pancreatic cancer and autophagy remain unclear. HMGB1, an abundant architectural chromosomal protein and autophagic regulator, is a promising therapeutic target for cancer treatment. We generated exciting preliminary data indicating that conditional genetic ablation of HMGB1 in the pancreas renders mice extraordinarily sensitive to oncogenic K-Ras-driven pancreatic carcinogenesis as well as autophagy deficient. These exciting findings raise several important questions regarding the novel mechanisms underlying the regulation of pancreatic cancer and autophagy. We hypothesize that HMGB1 is a central regulator for this association between pancreatic cancer and autophagy. We propose the following specific aims: Aim 1. Define the mechanism causing pancreatic tumorigenesis when HMGB1-mediated autophagy is defective. Aim 2. Determine whether antioxidant treatment or blocking the activity of extracellular histones can help prevent pancreatic cancer development when HMGB1-mediated autophagy is defective. Collectively, the findings from this study will reveal a previously unrecognized molecular mechanism through which HMGB1-dependent autophagy may impact the progression of pancreatic cancer. Importantly, this study may uncover novel molecular targets that could lead to more effective treatments for pancreatic cancer.