CCL28-induced RAR[beta] expression inhibits oral squamous cell carcinoma bone invasion

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of [beta]-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-[beta] (RAR[beta]) expression by reducing the interaction between RAR[alpha] and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RAR[beta] expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RAR[beta] expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RAR[beta] had significantly better overall survival. These findings suggest that CCL28, CCR10, and RAR[beta] are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.
Introduction Oral squamous cell carcinoma (OSCC), which accounts for 40% of all head and neck squamous cell carcinoma (HNSCC) cases, not only frequently metastasizes to distant sites but also invades [...]