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-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-Ras^G12D/+;Hmgb1^-/- mice. Pharmacological inhibition of HMGB1 loss by glycyrrhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in PDAC.

中文翻译：

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细胞内HMGB1作为胰腺癌的新型肿瘤抑制因子。

尽管现代医学取得了新进展，但由致癌性K-Ras驱动的胰腺导管腺癌（PDAC）仍然是最致命的人类癌症之一。PDAC的发病机制部分归因于固有的染色体不稳定性和外在的炎症激活。然而，胰腺癌发生中这两个事件之间的分子联系尚未完全建立。在这里，我们显示细胞内高迁移率族盒1（HMGB1）通过抑制染色体不稳定性介导的促炎性核小体释放，显着抑制致癌性K-Ras驱动的胰腺肿瘤发生。胰腺中HMGB1单等位基因或两个等位基因的有条件遗传消融使小鼠对出生时致癌性K-Ras驱动的前体病变（包括胰腺上皮内肿瘤）极为敏感，导管内乳头状粘液性肿瘤和粘液性囊性肿瘤。胰腺中HMGB1的丢失与氧化性DNA损伤和染色体不稳定性有关，其特征是染色体重排和端粒异常。这些导致炎性核小体释放并传播K-Ras驱动的胰腺肿瘤发生。细胞外核小体通过浸润巨噬细胞/嗜中性粒细胞促进白介素6（IL-6）分泌，并增强胰腺病变中的致癌性K-Ras信号传导。抗IL-6或组蛋白H3的中和抗体或晚期糖基化终产物受体的敲除均限制了K-Ras信号的激活，防止了癌症的发展和转移/侵袭，并延长了Pdx1-Cre; K-Ras的动物存活 胰腺中HMGB1的丢失与氧化性DNA损伤和染色体不稳定性有关，其特征是染色体重排和端粒异常。这些导致炎性核小体释放并传播K-Ras驱动的胰腺肿瘤发生。细胞外核小体通过浸润巨噬细胞/嗜中性粒细胞促进白介素6（IL-6）分泌，并增强胰腺病变中的致癌性K-Ras信号传导。抗IL-6或组蛋白H3的中和抗体或晚期糖基化终产物受体的敲除均限制了K-Ras信号的激活，防止了癌症的发展和转移/侵袭，并延长了Pdx1-Cre; K-Ras的动物存活 胰腺中HMGB1的丢失与氧化性DNA损伤和染色体不稳定性有关，其特征是染色体重排和端粒异常。这些导致炎性核小体释放并传播K-Ras驱动的胰腺肿瘤发生。细胞外核小体通过浸润巨噬细胞/嗜中性粒细胞促进白介素6（IL-6）分泌，并增强胰腺病变中的致癌性K-Ras信号传导。抗IL-6或组蛋白H3的中和抗体或晚期糖基化终产物受体的敲除均限制了K-Ras信号的激活，防止了癌症的发展和转移/侵袭，并延长了Pdx1-Cre; K-Ras的动物存活 这些导致炎性核小体释放并传播K-Ras驱动的胰腺肿瘤发生。细胞外核小体通过浸润巨噬细胞/嗜中性粒细胞促进白介素6（IL-6）分泌，并增强胰腺病变中的致癌性K-Ras信号传导。抗IL-6或组蛋白H3的中和抗体或敲除高级糖基化终产物的受体都限制了K-Ras信号的激活，防止了癌症的发展和转移/侵袭，并延长了Pdx1-Cre; K-Ras的动物存活 这些导致炎性核小体释放并传播K-Ras驱动的胰腺肿瘤发生。细胞外核小体通过浸润巨噬细胞/嗜中性粒细胞促进白介素6（IL-6）分泌，并增强胰腺病变中的致癌性K-Ras信号传导。抗IL-6或组蛋白H3的中和抗体或晚期糖基化终产物受体的敲除均限制了K-Ras信号的激活，防止了癌症的发展和转移/侵袭，并延长了Pdx1-Cre; K-Ras的动物存活^{G12D / +}； Hmgb1 ^-/-小鼠。甘草甜素对HMGB1丢失的药理抑制作用限制了炎症条件下小鼠中致癌性K-Ras驱动的肿瘤发生。PDAC患者中HMGB1的核表达和总细胞表达降低与总体存活率差相关，支持细胞内HMGB1作为一种新型的肿瘤抑制因子，与PDAC的预后和治疗意义相关。