High mobility group box 1 induces bone pain associated with bone invasion in a mouse model of advanced head and neck cancer

Advanced head and neck cancer (HNC) can invade facial bone and cause bone pain, thus posing a significant challenge to the quality of life of patients presenting with advanced HNC. The present study was designed to investigate HNC bone pain (HNC-BP) in an intratibial mouse xenograft model that utilized an HNC cell line (SAS cells). These mice develop HNC-BP that is associated with an expression of phosphorylated ERK1/2 (pERK1/2), which is a molecular indicator of neuron excitation in dorsal root ganglia (DRG) sensory neurons. Our experiments demonstrated that the inhibition of high mobility group box 1 (HMGB1) by short hairpin (shRNA) transduction, HMGB1 neutralizing antibody, and HMGB1 receptor antagonist suppressed the HNC-BP and the pERK1/2 expression in DRG. It was also observed that HNC-derived HMGB1 increased the expression of the acid-sensing nociceptor, transient receptor potential vanilloid 1 (TRPV1), which is a major cause of osteoclastic HNC-BP in DRG. Collectively, our results demonstrated that HMGB1 originating in HNC evokes HNC-BP via direct HMGB1 signaling and hypersensitization for the acid environment in sensory neurons.