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 β-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-β (RARβ) expression by reducing the interaction between RARα 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. RARβ expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARβ expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARβ had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARβ 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.
Bibliographical noteFunding Information:
We thank Chae-Eun Lee from the Oral Science Research Institute for providing technical assistance with μCT. This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1901).
We thank Chae-Eun Lee from the Oral Science Research Institute for providing technical assistance with ?CT. This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C1901).
bone invasion. Intraperitoneally administered CCL28 prevented osteolysis in athymic nude mice inoculated with OSCC cells. The anti-osteoclastogenic activity of CCL28 was supported by the reduced number of TRAP-positive osteoclasts detected at the interface between tumor and bone tissues. Tumor growth was also inhibited by CCL28 treatment, and the in vivo inhibitory activity of CCL28 on tumor growth may be due to a decrease in the release of bone matrix–derived growth factors by osteoclast-mediated bone resorption rather than the direct inhibition of OSCC cell viability. Increased RARβ expression was detected in the tumor tissues of CCL28-treated mice. Furthermore, we confirmed that CCL28 overexpression in OSCC cells can also reduce tumor growth and osteolysis. These findings support the in vitro results demonstrating that CCL28 inhibits OSCC bone invasion by upregulating RARβ.
Copyright: © 2019, American Society for Clinical Investigation.
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