α7 nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway.
α7 nicotinic acetylcholine receptor in tumor-associated macrophages inhibits colorectal cancer metastasis through the JAK2/STAT3 signaling pathway.
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肿瘤相关巨噬细胞中的α7烟碱乙酰胆碱受体通过JAK2/STAT3信号通路抑制结直肠癌转移。
DOI：
10.3892/or.2017.5935
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发表时间：
2017-11
期刊：
影响因子：
4.2
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Fei R;Zhang Y;Wang S;Xiang T;Chen W
大量证据表明α7烟碱受体亚型在慢性炎症和神经病理性疼痛信号传导中起重要作用。本研究的目的是确定肿瘤相关巨噬细胞（TAMs）中内源性α 7 nAChR信号在人结直肠癌（CRC）转移和预后中的作用。本文观察了51例大肠癌患者原发癌细胞及癌旁间质细胞，尤其是TAM中α 7 nAChR的表达。使用α 7 nAChR-siRNA敲除（TMα7-/-）的人单核细胞THP衍生巨噬细胞（TM）和CRC细胞Transwell共培养模型，测定了两种CRC细胞LoVo和SW 620的迁移和侵袭。采用Western blotting检测模拟TAMs中NF-κB、STAT 3、PI 3 K信号通路相关分子的表达，TM暴露于间接LoVo细胞刺激。应用烟碱型α7受体拮抗剂[α-银环蛇毒素（α-Btx）]和三种药物抑制剂：AG 490（JAK 2/STAT 3抑制剂）、LY 294002（PI 3 K抑制剂）和Bay 11-7082（NF-κB抑制剂）来评价这些信号通路是否与α 7 nAChR敲低TM共培养时CRC细胞的迁移增强相关。结果表明，不同患者TAM中α 7 nAChR的表达存在差异。而肝转移发生率高的结直肠癌患者TAMs中α 7 nAChR无表达或低表达。α 7 nAChR-siRNA敲低的TM（TMα7−/−）显著增强了两种CRC细胞系LoVo和SW 620的迁移和侵袭。α 7 nAChR基因敲低可显著下调与LoVo细胞共培养后STAT 3、PI 3 K p85和NF-κB p65的磷酸化水平。JAK 2/STAT 3的抑制阻止了TMα7−/−增强的LoVo细胞迁移。α 7 nAChR在结直肠癌患者TAM中的表达在防止转移中起重要作用，并且可能是结直肠癌的预后标志物，其可能受JAK 2/STAT 3信号通路的调节。
Considerable evidence has implied that α7 nicotinic receptor subtypes play an important role in chronic inflammatory and neuropathic pain signaling. The aim of the present study was to determine the role of endogenous α7nAChR signaling in tumor-associated macrophages (TAMs) in human colorectal cancer (CRC) metastasis and prognosis. α7nAChR expression in primary tumor cells and adjacent stroma cells especially in TAMs in 51 CRC patients was observed. Using a human monocyte THP-derived macrophages (TMs) with α7nAChR-siRNA knockdown (TMα7−/−) and a CRC cell Transwell co-culture model, the migration and invasion of two CRC cells, LoVo and SW620, were determined. Western blotting was carried out to investigate the expression of multiple molecules involved in the NF-κB, STAT3, PI3K signaling pathways in mimic TAMs, i.e., TMs exposed to in-direct LoVo cell stimulation. A nicotinic α7 receptor antagonist [α-bungarotoxin (α-Btx)] and three pharmaceutical inhibitors: AG490 (JAK2/STAT3 inhibitor), LY294002 (PI3K inhibitor) and Bay 11–7082 (NF-κB inhibitor) were applied to evaluate whether these signaling pathways were associated with the enhanced migration of CRC cells when co-cultured with α7nAChR knockdown TMs. The results revealed that the expression of α7nAChR in TAMs differed in patients. However, CRC patients who had a high incidence of hepatic metastasis showed no or low expression of α7nAChR in TAMs. TMs with α7nAChR-siRNA knockdown (TMα7−/−) significantly enhanced the migration and invasion of the two CRC cell lines LoVo and SW620. α7nAChR knockdown in TMs significantly downregulated phosphorylation of STAT3, PI3K p85 and NF-κB p65 after co-culturing with LoVo cells. Inhibition of JAK2/STAT3 prevented the TMα7−/−-enhanced migration of LoVo cells. α7nAChR expressed in TAMs in human CRC patients plays an important role in preventing metastasis and could be a prognostic marker in CRCs, which may be regulated by the JAK2/STAT3 signaling pathway.
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影响因子：
2.8
作者：
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通讯作者：
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