title: C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kaida
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kitano
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Arima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Izumi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Imai
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hashimoto
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Chikamoto
authors.affiliation: Department of Molecular Pathology, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Imanura
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Ishiko
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Beppu
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement; D015936:Complement C5a / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a; D020742:rhoA GTP-Binding Protein
keywords: C5a receptor; CD88; RhoA; gastric cancer