C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA
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Takayoshi Kaida1, Hidetoshi Nitta1, Yuki Kitano1, Kensuke Yamamura1, Kota Arima1, Daisuke Izumi1, Takaaki Higashi1, Junji Kurashige1, Katsunori Imai1, Hiromitsu Hayashi1, Masaaki Iwatsuki1, Takatsugu Ishimoto1, Daisuke Hashimoto1, Yoichi Yamashita1, Akira Chikamoto1, Takahisa Imanura2, Takatoshi Ishiko1, Toru Beppu1, Hideo Baba1
1Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
2Department of Molecular Pathology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
Hideo Baba, email: [email protected]
Keywords: C5a receptor, CD88, RhoA, gastric cancer
Abbreviations: C5aR, C5a receptor; GC, Gastric cancer; rC5a, recombinant human complement component C5a; GDP, guanosine diphosphate; GTP, guanosine triphosphate
Received: March 14, 2016 Accepted: October 01, 2016 Published: October 14, 2016
Purpose: 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.
Experimental Design: 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.
Results: 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 68.5%, respectively (p=0.008).
Conclusions: 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.
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