Dental Journal of Iwate Medical University
Online ISSN : 2424-1822
Print ISSN : 0385-1311
ISSN-L : 0385-1311
Original Article
Sclerostin derived from EMT-promoted human oral squamous cell carcinoma cells induces IL-6- and IL-17A-mediated M1 to M2 polarization shift in THP-1-derived macrophages
Yuudai ISHIKAWATaifu HIRANOHiroyuki YAMADAAkira ISHISAKIMasaharu KAMO
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2022 Volume 47 Issue 1 Pages 34-50

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Abstract

Squamous cell carcinoma (SCC) is the most common cancer in the oral cavity. Epithelial–mesenchymal transition (EMT) plays an important role in SCC cell metastasis process. We have previously demonstrated that transforming growth factor-β1 (TGF-β1) induces EMT in HSC-4, a human oral SCC (hOSCC) cell line. However, the molecular mechanisms of metastasis after EMTpromoted cancer are poorly understood. On the other hand, tumor-associated macrophages (TAMs)that coexist with cancer tissue participate in permeation metastasis. However, whether TAMs affect hOSCC cell metastasis in the tumor microenvironment (TME) remains uncertain. Here, we investigated the expression status of inflammatory and anti-inflammatory cytokines and M2 polarization status in macrophages (Mφs) cocultured with EMT-promoted HSC-4 cells. Under coculture of EMT-promoted HSC-4 cells and M1-Mφs, we found that the expression of tumor necrosis factor-α (TNF-α), an M1-polarization inducer, was clearly suppressed in M1-Mφ, while the expression of M2-polarization promoter TGF-β1 and M2-Mφ marker CD163 was significantly reinforced. These results indicate that M1-Mφ polarization into M2-Mφ was promoted by coculture with EMT-promoted HSC-4 cells. In the next step, we tried to identify the factors derived from EMTpromoted HSC-4 cells that promoted M2-Mφ polarization. We found that 1) TGF-β1 induces sclerostin expression through the Smad signal transduction pathway in HSC-4 cells, 2) sclerostin reinforces interleukin-6 (IL-6), TGF-β1, and IL-17A expression in M1-Mφs, 3) IL-6 promotes IL-17A expression in M1-Mφs and M1-Mφ polarization into M2-Mφ, and 4) IL-17A reinforces M1-Mφ polarization into M2-Mφ. These results strongly suggest that the EMT-promoted hOSCC cells retained the ability to promote polar changes from M1-Mφs to M2-Mφs through sclerostin production in the TME.

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2022 The Dental Society of Iwate Medical University
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