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-Ras signaling activation, prevent cancer development and metastasis/invasion, and prolong animal survival in Pdx1-Cre;K-RasG12D/+;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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of all pancreatic malignancies
Given that pancreatitis is considered one of the major risk factors for PDAC [25], we postulated that high mobility group box 1 (HMGB1) would regulate K-Ras-driven pancreatic tumorigenesis and generated mice conditionally defective in both K-Ras and Hmgb1 in the pancreatic tissue (Pdx1Cre;K-Ras ; G12D/+ Hmgb1−/−, termed KCH mice; Supplementary information, Figure S1)
These findings indicate that HMGB1 is involved in K-Ras-driven pancreatic cancer development
Summary
Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of all pancreatic malignancies. Oncogenic K-Ras plays a central role in controlling PDAC initiation and progression, the ability of mutant K-Ras to drive PDAC was not successfully investigated until the generation of mice with a Cre-inducible conditional allele (Pdx1-Cre;K-RasG12D/+, termed KC mice) targeting the endogenous K-Ras locus [12]. These KC mice develop lesions that slowly progress into advanced PDAC and have a median survival of 15 months [12], suggesting that K-Ras activation is a tumor-initiating event that requires other elements that accelerate PDAC progression. Further understanding of K-Ras signaling and regulation may translate into improved treatments for pancreatic cancer
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