High-mobility group box 1 induces bone destruction associated with advanced oral squamous cancer via RAGE and TLR4

Biochem Biophys Res Commun. 2020 Oct 20;531(3):422-430. doi: 10.1016/j.bbrc.2020.07.120. Epub 2020 Aug 14.

Abstract

Bone destruction of maxillary and mandibular bone by invasive oral squamous cell cancer (OSCC) raises various problems in the management of patients, resulting in poor outcomes and survival. However, the mechanism behind bone destruction by OSCC remains unclear. High-mobility group box 1 (HMGB1), a highly conserved ubiquitous nuclear non-histone DNA-binding protein, has been demonstrated to be secreted by aggressive cancers and regulate osteoclastogenesis, a central player during bone destruction. We therefore reasoned that HMGB1 secreted by OSCCs contributes to bone destruction. Our results showed that HMGB1 is produced by human cell lines of OSCC and promotes osteoclastogenesis via up-regulation of the expression of receptor activator of nuclear factor kappa-Β ligand in osteoblasts and osteocytes, and consequently osteoclastic bone destruction in mice. Further, we found that these actions of HMGB1 are mediated via the receptor for advanced glycation end products and toll-like receptors. These findings suggest that HMGB1 of OSCC and its down-stream signal pathways are potential targets for the treatment of bone destruction associated with advanced OSCC.

Keywords: Bone destruction; HMGB1; Oral squamous cell cancer; Osteoclasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Bone Resorption / pathology
  • Bone and Bones / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • HMGB1 Protein / metabolism*
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteocytes / drug effects
  • Osteocytes / metabolism
  • Osteogenesis / drug effects
  • RANK Ligand / metabolism
  • RAW 264.7 Cells
  • Receptor for Advanced Glycation End Products / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Sulfonamides / pharmacology
  • Toll-Like Receptor 4 / antagonists & inhibitors
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Benzamides
  • FPS-ZM1
  • HMGB1 Protein
  • Ki-67 Antigen
  • RANK Ligand
  • Receptor for Advanced Glycation End Products
  • Sulfonamides
  • Toll-Like Receptor 4
  • ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate