Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer

作者：Rui Kang, Yangchun Xie, Qiuhong Zhang, Wen‐Chi Hou, Qingping Jiang, Shan Zhu, Jinbao Liu, Dexing Zeng, Haichao Wang, David L. Bartlett, Timothy R. Billiar, Herbert J. Zeh, Michael T. Lotze, Daolin Tang · 发表于：Cell Research · 年份：2017 · DOI：10.1038/cr.2017.51 · 被引用次数：138 · 研究领域：Advanced Glycation End Products research、Drug Transport and Resistance Mechanisms、Immune cells in cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 (HMGB1) remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both alleles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mucinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extracellular nucleosomes promote interleukin 6 (IL-6) secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glycation end products all limit K-R...