CCL20 derived from PMA-differentiated macrophages abrogates TGF-β1-induced expression of cancer progression suppressor CXCL14 in HSC-4 cells in PI3K-, MEK1/2-, and NF-κB-dependent manners

抄録

Squamous cell carcinoma（ SCC） is the most common cancer that develops in the oral cavity. Epithelial-mesenchymal transition（ EMT） is known to play an important role in the process of metastasis of SCC cells. In our previous study, we demonstrated that transforming growth factor-β1 （TGF-β1） induces EMT in the human oral SCC（ hOSCC） cell line HSC-4. However, the molecular mechanisms of the metastasis after an EMT-induced cancer are poorly understood. Moreover, tumorassociated macrophages（ TAMs）, which coexist with the cancer tissues, are known to participate in permeation metastasis. However, it still remains uncertain whether TAMs affect the metastatic activity of hOSCC cells. We found that the expression of CXCL14, which is known to suppress the progression of colon, and breast cancers, was upregulated in HSC-4 cells by TGF-β1 stimulation. The Smad3 inhibitor, SIS3, suppressed the TGF-β1-induced expression of CXCL14. Interestingly, the CXCL14 suppressed the migratory and proliferative activities in HSC-4 cells. Moreover, the expression of CXCL14 in HSC-4 cells was downregulated by cocultivation with differentiated macrophages derived from monocytic THP-1 cells, but not by cocultivation with non-differentiated monocytic THP-1 cells. On the other hand, we found that expression levels of CCL20 in the differentiated macrophages derived from THP-1 cells was higher than that in non-differentiated monocytic THP-1 cells. In addition, CCL20 suppressed TGF-β1-induced expression of CXCL14. Intriguingly, the MAPK/ERK kinase （MEK） inhibitor U0126, PI3K inhibitor LY294002, or NF-κB kinase-2（ IKK-2） inhibitor TPCA-1　abrogated the CCL20-promoted inhibition of TGF-β1-induced expression of CXCL14. Moreover, CCL20 decreased the migratory activity of HSC-4 cells. Taken together, these results suggest that CCL20 derived from TAMs abrogated the TGF-β1-induced expression of the cancer progression suppressor CXCL14 in HSC-4 cells in PI3K-, MEK1/2-, and NF- κB-dependent manners, resulting in the activation of metastatic activity in HSC-4 cells.