Purpose: Anaphylatoxin C5α is a strong chemoattractant of the complement system that binds the C5α receptor (C5αR). The expression of C5αR is associated with poor prognosis in several cancers. However, the role of C5αR in gastric cancer (GC) is unknown. The aim of this study was to examine the role of C5αR on GC cell motility and invasion. Experimental Design: The mechanism of invasion via C5αR was assessed by analyzing cytoskeletal rearrangement and RhoA activity after C5α treatment. Moreover, we investigated the relationship between C5αR expression and the prognosis of GC patients. Results: Two human GC cell lines (MKN1 and MKN7) had high C5αR expression. An invasion assay revealed that C5α stimulation promoted the invasive ability of MKN1 and MKN7 cells and that this was suppressed by knockdown of C5αR using siRNA or a C5αR-antagonist. Moreover, overexpression of C5αR in GC cells enhanced the conversion of RhoA-guanosine diphosphate (RhoA-GDP) to RhoA-guanosine triphosphate (RhoA-GTP) after C5α 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 C5αR 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 C5αR expression was 58.2% and 88.5%, respectively (p=0.008). Conclusions: This study is the first to demonstrate that C5αR 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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