S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways
S100A8/A9 Induced by Interaction with Macrophages in Esophageal Squamous Cell Carcinoma Promotes the Migration and Invasion of Cancer Cells via Akt and p38 MAPK Pathways
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DOI：
10.1016/j.ajpath.2021.12.002
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发表时间：
2022-02-25
影响因子：
6
通讯作者：
Yokozaki, Hiroshi
中科院分区：
文献类型：
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作者：
Tanigawa, Kohei;Tsukamoto, Shuichi;Yokozaki, Hiroshi
肿瘤相关巨噬细胞与食管鳞状细胞癌（ESCC）细胞的恶性表型相关。以前，ESCC细胞和巨噬细胞的间接共培养试验用于鉴定与ESCC进展相关的几个因素。在此，建立了ESCC细胞和巨噬细胞的直接共培养测定，其更接近地模拟实际癌症微环境。直接共培养的食管鳞癌细胞的迁移和侵袭能力，Akt和p38丝裂原活化蛋白激酶（MAPK）的磷酸化水平显着增加相比，单培养的食管鳞癌细胞。根据单培养和共培养的ESCC细胞之间的cDNA微阵列分析，在共培养的ESCC细胞中，通常作为异源二聚体（本文中，S100 A8/A9）存在并起作用的S100钙结合蛋白A8和A9（S100 A8和S100 A9）的表达和释放均显著增强。加入重组人S100 A8/A9蛋白通过Akt和p38 MAPK信号转导诱导ESCC细胞迁移和侵袭。S100 A8和S100 A9沉默抑制共培养的ESCC细胞的迁移、侵袭和Akt和p38 MAPK的磷酸化。此外，S100 A8/A9高表达的ESCC患者的无病生存期（P = 0.005）和病因特异性生存期（P = 0.038）显著缩短。这些结果表明，S100 A8/A9在ESCC细胞中的表达和释放通过与巨噬细胞直接共培养而增强，并且S100 A8/A9通过Akt和p38 MAPK信号通路促进ESCC进展。
Tumor-associated macrophages are associated with more malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. Previously, an indirect co-culture assay of ESCC cells and macrophages was used to identify several factors associated with ESCC progression. Herein, a direct co-culture assay of ESCC cells and macrophages was established, which more closely simulated the actual cancer microenvironment. Direct co-cultured ESCC cells had significantly increased migration and invasion abilities, and phosphorylation levels of Akt and p38 mitogen-activated protein kinase (MAPK) compared with monocultured ESCC cells. According to a cDNA microarray analysis between monocultured and co cultured ESCC cells, both the expression and release of S100 calcium binding protein A8 and A9 (S100A8 and S100A9), which commonly exist and function as a heterodimer (herein, S100A8/A9), were significantly enhanced in co-cultured ESCC cells. The addition of recombinant human S100A8/A9 protein induced migration and invasion of ESCC cells via Akt and p38 MAPK signaling. Both S100A8 and S100A9 silencing suppressed migration, invasion, and phosphorylation of Akt and p38 MAPK in co cultured ESCC cells. Moreover, ESCC patients with high S100A8/A9 expression exhibited significantly shorter disease-free survival (P = 0.005) and cause-specific survival (P = 0.038). These results suggest that S100A8/A9 expression and release in ESCC cells are enhanced by direct co-culture with macrophages and that S100A8/A9 promotes ESCC progression via Akt and p38 MAPK signaling pathways.