CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasion
Junhee Park, … , Kwang-Kyun Park, Won-Yoon Chung
Junhee Park, … , Kwang-Kyun Park, Won-Yoon Chung
Published September 5, 2019
Citation Information: J Clin Invest. 2019;129(12):5381-5399. https://doi.org/10.1172/JCI125336.
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Research Article Oncology

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

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.

Authors

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

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Figure 3

The CCL28/CCR10 axis inhibits OSCC cell invasion by activating RAR signaling.

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The CCL28/CCR10 axis inhibits OSCC cell invasion by activating RAR signa...
(A) Representative pathway reporter array (n = 2) for wild-type and CCR10-knockdown (KD) OSCC cells in the absence or presence of CCL28 (20 ng/mL). Reporter gene activities in CCL28-treated cells were normalized by those in untreated cells and represented as fold changes. (B) Correlations between CCL28 mRNA expression and RARβ mRNA expression in patients with HNSCC by Pearson’s correlation analysis. Scatter plots represent normalized RSEM values for each gene. (C) RARβ and RARβ2 expression in response to CCL28 treatment (20 pg/mL) in Ca9.22, YD10B, HSC2, or HSC3 OSCC cells. (D) RARβ and RARβ2 expression in CCL28-overexpressing or CCL28-knockdown Ca9.22 or YD10B OSCC cells. (E) RARβ expression in response to CCL28 treatment (20 pg/mL) in CCR3- or CCR10-downregulated Ca9.22 or YD10B OSCC cells. (C–E) Representative Western blot images. (F) Invasion of OSCC cells treated with the RARβ-selective antagonist LE135 or the inverse pan-RAR agonist BMS493 in the presence of CCL28 (20 pg/mL) (mean ± SEM, n = 3). *P < 0.05 and **P < 0.005 versus CCL28-untreated cells; #P < 0.05 and ##P < 0.01 versus CCL28-only-treated cells by 1-way ANOVA with multiple-comparisons test.