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 4

CCL28 upregulates RARβ expression via RARα-mediated transcription by reducing the interaction between RARα and HDAC1.

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CCL28 upregulates RARβ expression via RARα-mediated transcription by red...
(A) RARβ and RARβ2 expression levels in OSCC cells treated with CCL28 (20 pg/mL) and/or the selective RARα antagonist ER50891 (ER). (B) Invasion of OSCC cells treated with CCL28 (20 pg/mL) and/or the selective RARα antagonist ER50891 (ER) (mean ± SEM, n = 3). *P < 0.001 versus CCL28-untreated control cells; #P < 0.005 and ##P < 0.001 versus CCL28-only-treated cells by 1-way ANOVA with multiple-comparisons test. (C) Interaction between RARα and HDACs or DNMT in OSCC cells treated with CCL28 (20 pg/mL). Immune complexes were obtained using a Pierce Co-IP kit. (A and C) Representative Western blot images. (D) Acetylated histone H3 levels and HDAC1 interaction at the RARB promoter region of OSCC cells treated with CCL28 (20 pg/mL). Histone modification (H3K9ac) and HDAC1 binding were analyzed by ChIP-qPCR. Data are presented as the percentage of the total chromatin input (% input), and graphs are representative.