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.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 13

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

×

Figure 5

CCL28 treatment reduces the RANKL/OPG ratio in OSCC cells and osteoblasts and RANKL-induced differentiation of osteoclast precursors.

Options: View larger image (or click on image) Download as PowerPoint
CCL28 treatment reduces the RANKL/OPG ratio in OSCC cells and osteoblast...
(A) RANKL and OPG levels secreted by CCL28-treated OSCC cells into the culture media, and the RANKL/OPG ratio (mean ± SEM, n = 3). *P < 0.05 vs. CCL28-untreated cells by 2-tailed Student’s t test. (B) RANKL levels secreted by OSCC cells treated with the selective RARα antagonist ER50891 or the RARβ antagonist LE135 in the presence of CCL28 (mean ± SEM, n = 3). *P < 0.05 versus CCL28-untreated cells; #P < 0.05 versus CCL28-only-treated cells by 1-way ANOVA with multiple comparisons test. (C) RANKL and OPG levels secreted by CCL28-treated osteoblasts into the culture media, and the RANKL/OPG ratio (mean ± SEM, n = 3). *P < 0.05 and **P < 0.01 versus CCL28-untreated cells by 1-way ANOVA with multiple comparisons test. (D) Secreted levels of RANKL and OPG by CCL28-treated osteoblasts in the presence of conditioned media (CM) from OSCC cell lines, and the RANKL/OPG ratio (mean ± SEM, n = 3). #P < 0.05 and ##P < 0.01 versus control cells without CM; *P < 0.05 versus CM-only-treated cells by 1-way ANOVA with multiple-comparisons test. (E) Osteoclast formation in CCL28-treated BMMs in the presence of RANKL (mean ± SEM, n = 3). Representative images at ×100 original magnification. *P < 0.05 versus RANKL-only-treated cells by 1-way ANOVA with multiple comparisons test.