title: Intracellular HMGB1 as a novel tumor suppressor of pancreatic 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-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.
authors.affiliation: The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.|Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Yangchun
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Hou
authors.affiliation: The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Dexing
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism*; D043171:Chromosomal Instability; D015331:Cohort Studies; D004249:DNA Damage; D011905:Genes, ras / Q000235:genetics; D019695:Glycyrrhizic Acid / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental; D009707:Nucleosomes / Q000378:metabolism; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D009707:Nucleosomes; D025521:Tumor Suppressor Proteins; D019695:Glycyrrhizic Acid