CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasion.

Junhee Park,Won-Yoon Chung,Jae Hoon Shim,Seung Hwa Son,Na-Young Song,Xianglan Zhang,Ki Rim Kim,Kwang-Kyun Park,Sun Kyoung Lee

doi:10.1172/jci125336

Abstract

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.

Highlights

Oral squamous cell carcinoma (OSCC), which accounts for 40% of all head and neck squamous cell carcinoma (HNSCC) cases, frequently metastasizes to distant sites and invades the maxillary or mandibular bone based on its anatomically close proximity to the jaw bone [1, 2]
Increased CCL28 protein levels were confirmed in RUNX3-knockdown Ca9.22 and YD10B OSCC cells (Supplemental Figure 1A) and in the tumor tissues of RUNX3-knockdown Ca9.22 cell–injected mice obtained from our previous study (Supplemental Figure 1B)
The invasion of Ca9.22 and YD10B cells was markedly inhibited by CCL28 treatment in the absence or presence of TGF-β, one of the abundantly stored growth factors in the bone matrix that is released by osteoclastic bone resorption (Figure 1A), whereas the invasion of RUNX3-nonexpressing HSC2 and HSC3 cells was not (Supplemental Figure 3A)

Summary

Introduction

Oral squamous cell carcinoma (OSCC), which accounts for 40% of all head and neck squamous cell carcinoma (HNSCC) cases, frequently metastasizes to distant sites and invades the maxillary or mandibular bone based on its anatomically close proximity to the jaw bone [1, 2]. The invading tumor cells change the bone microenvironment by secreting TNF-α, interleukins, parathyroid hormone–related protein (PTHrP), and chemokines, which activate osteoclasts directly and/or stimulate RANKL expression in stromal stem cells and osteoblasts [6, 7]. We further evaluated whether the CCL28/ CCR10/RARβ axis is involved in bone invasion using murine models and tumor tissues of patients with OSCC. To our knowledge, this is the first report verifying the role of CCL28 in cancer cell– mediated bone destruction

Results

Discussion

Methods