title: High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity.
abstract: Liver inflammation plays a critical role in hepatocellular carcinoma (HCC) etiology. Damage-associated molecular patterns (DAMP), such as high-mobility group box 1 (HMGB1), and dysregulated miRNAs involved in inflammatory disease states, such as miR-21, may participate in the link between inflammation and cancer. We sought to determine the role of HMGB1 signaling in HCC tumor progression. We first document the concordant expression increase of HMGB1 and miR-21 in HCC cell lines and primary HCC tumor samples and subsequently show that HMGB1 stimulation results in overexpression of miR-21. These changes were found to be dependent on the IL6/STAT3 signaling axis. Invasion and migration of HCC cells in vitro were inhibited by both STAT3 and miR-21 antagonists, suggesting a role for this pathway in HCC tumor progression. We verified that HMGB1-induced expression of miR-21 in HCC provides a posttranscriptional repression of the matrix metalloproteinase (MMP) inhibitors RECK and TIMP3, which are known to impact HCC progression and metastases. Finally, we found that inhibition of miR-21 in murine HMGB1-overexpressing HCC xenografts led to reduced tumor MMP activity through released repression of the miR-21 targets RECK and TIMP3, which ultimately impeded tumor progression. The prototypical DAMP, HMGB1, is released during liver inflammation and provides a favorable environment for HCC growth. HMGB1 signaling increases miR-21 expression to mediate the enhanced activity of MMPs through RECK and TIMP3. These findings provide a novel mechanism for HMGB1-mediated HCC progression through the IL6/Stat3-miR-21 axis.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Man
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. Department of Gastroenterology, The First Affiliated Hospital of Gannan Medical College, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Patrick
authors.initials: P
authors.lastname: Varley
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: He
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.affiliation: Institute of Liver Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. tsunga@upmc.edu jslin@tjh.tjmu.edu.cn.
authors.forename: Jusheng
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. tsunga@upmc.edu jslin@tjh.tjmu.edu.cn.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D058851:GPI-Linked Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D024243:HMGB1 Protein / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism
chemical_list: D058851:GPI-Linked Proteins; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C115460:RECK protein, human; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases