C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA.
C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA.
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DOI：
10.18632/oncotarget.12656
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发表时间：
2016-12-20
期刊：
影响因子：
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通讯作者：
Baba H
中科院分区：
文献类型：
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作者：
Kaida T;Nitta H;Kitano Y;Yamamura K;Arima K;Izumi D;Higashi T;Kurashige J;Imai K;Hayashi H;Iwatsuki M;Ishimoto T;Hashimoto D;Yamashita Y;Chikamoto A;Imanura T;Ishiko T;Beppu T;Baba H
过敏毒素C5 a是补体系统的一种强化学引诱物，可结合C5 a受体（C5 aR）。C5 aR的表达与几种癌症的不良预后相关。然而，C5 aR在胃癌（GC）中的作用尚不清楚。本研究的目的是研究C5 aR对胃癌细胞运动和侵袭的作用。通过分析C5 a处理后的细胞骨架重排和RhoA活性来评估通过C5 aR的侵袭机制。此外，我们还研究了C5 aR表达与胃癌患者预后的关系。两种人胃癌细胞系（MKN 1和MKN 7）具有高C5 aR表达。侵袭测定显示，C5 a刺激促进MKN 1和MKN 7细胞的侵袭能力，并且这通过使用siRNA或C5 aR拮抗剂敲低C5 aR来抑制。此外，在GC细胞中过表达C5 aR增强了C5 a刺激后RhoA-鸟苷二磷酸（RhoA-GDP）向RhoA-鸟苷三磷酸（RhoA-GTP）的转化，并引起形态学变化，包括应力纤维和丝状伪足表达增加。对100例胃癌患者肿瘤标本的检查显示，C5 aR高表达（35/100，35.0%）与浸润深度增加、血管浸润和晚期相关。C5 aR高表达或低表达患者的5年总生存率分别为58.2%和88.5%（p=0.008）。这项研究首次证明C5 aR通过激活RhoA促进GC细胞侵袭，并与GC患者的不良预后相关。因此，本研究为需要高级治疗策略的GC患者提供了生物标志物。
Anaphylatoxin C5a is a strong chemoattractant of the complement system that binds the C5a receptor (C5aR). The expression of C5aR is associated with poor prognosis in several cancers. However, the role of C5aR in gastric cancer (GC) is unknown. The aim of this study was to examine the role of C5aR on GC cell motility and invasion. The mechanism of invasion via C5aR was assessed by analyzing cytoskeletal rearrangement and RhoA activity after C5a treatment. Moreover, we investigated the relationship between C5aR expression and the prognosis of GC patients. Two human GC cell lines (MKN1 and MKN7) had high C5aR expression. An invasion assay revealed that C5a stimulation promoted the invasive ability of MKN1 and MKN7 cells and that this was suppressed by knockdown of C5aR using siRNA or a C5aR-antagonist. Moreover, overexpression of C5aR in GC cells enhanced the conversion of RhoA-guanosine diphosphate (RhoA-GDP) to RhoA-guanosine triphosphate (RhoA-GTP) after C5a stimulation and caused morphological changes, including increased expression of stress fibers and filopodia. Examination of tumor specimens from 100 patients with GC revealed that high C5aR expression (35 of 100 samples, 35.0%) was associated with increased invasion depth, vascular invasion and advanced stage. The 5-year overall survival of patients with high or low C5aR expression was 58.2% and 88.5%, respectively (p=0.008). This study is the first to demonstrate that C5aR promotes GC cell invasion by activating RhoA and is associated with a poor prognosis in GC patients. Therefore, this study provides a biomarker for GC patients who require an advanced therapeutic strategy.