Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression
Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression
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补体 C5a/C5aR 通路通过下调 p21 表达增强胃癌的发病机制
DOI：
10.1016/j.canlet.2017.10.003
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Wu, Yu-Zhang
中科院分区：
文献类型：
--
作者：
Chen, Jian;Li, Gui-qing;Wu, Yu-Zhang
尽管补体C5 a/C5 aR通路在肿瘤发病中起着关键作用，但其潜在机制尚未完全阐明。在本研究中，我们发现在不同临床分期的胃癌患者中（从1期到IV期），肿瘤组织中的C5 aR和p-PI 3 K/AKT水平均显著高于邻近非肿瘤组织。与此相反，p21/p-p21水平显着低于肿瘤组织比在相邻的非肿瘤组织。体外重组C5 a显著促进p-PI 3 K/p-AKT的表达，但抑制p21/p-p21的表达。用C5 aR拮抗剂阻断C5 a/C5 aR信号转导可逆转C5 a诱导的对p21/p-p21表达的抑制作用。向用PI 3 K抑制剂预处理的细胞施用C5 a也阻止了这种抑制作用，表明PI 3 K/AKT信号传导途径参与了C5 a/C5 aR介导的p21/p-p21表达的抑制。体内C5 aR拮抗剂治疗导致小鼠肿瘤生长显著减少，伴随着p21/p-p21表达的显著升高和p-PI 3 K/AKT活化的降低。这些结果表明，C5 a/C5 aR通路通过激活PI 3 K/AKT信号转导抑制p21/p-p21表达而促进胃癌发病。(C)2017爱思唯尔B. V.保留所有权利。
Although the complement C5a/C5aR pathway is suggested to play a critical role in tumor pathogenesis, the underlying mechanism has yet to be fully elucidated. In the present study, we found that in patients with gastric cancer in different clinical stages (from stagelto stage IV), both C5aR and p-PI3K/AKT levels were significantly higher in tumoral tissues than in adjacent non-tumoral tissues. In contrast, p21/p-p21 levels were significantly lower in tumoral tissues than in adjacent non-tumoral tissues. In vitro recombinant C5a administration remarkably promoted p-PI3K/p-AKT expression, but inhibited p21/p-p21 expression. Blockage of C5a/C5aR signaling with a C5aR antagonist reversed the C5a-induced inhibitory effect on p21/p-p21 expression. C5a administration to cells pre-treated with a PI3K inhibitor also prevented this inhibitory effect, suggesting the involvement of the PI3K/AKT signaling pathway in C5a/C5aR-mediated suppression of p21/p-p21 expression. In vivo C5aR antagonist treatment caused significant reduction in tumor growth in mice, accompanied by a remarkable elevation in p21/p-p21 expression and reduction in p-PI3K/AKT activation. These results indicate that the C5a/C5aR pathway promotes gastric cancer pathogenesis by suppressing p21/p-p21 expression via activation of PI3K/AKT signaling. (C) 2017 Elsevier B.V. All rights reserved.