title: C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways.
abstract: The anaphylatoxin C5a is a chemoattractant for leukocyte migration via the C5a receptor (C5aR). We recently reported that C5aR was aberrantly expressed in a wide variety of human related cancers, while it also promotes cancer cell invasion by C5a stimulation. However, the biological significance of C5aR expression in renal cell carcinoma (RCC) has not yet been clarified. In the present study, we aimed to elucidate the biological role of C5aR in RCC progression. Clinical RCC specimens were analyzed for C5aR expression and its relationship with baseline demographic data and clinicopathological parameters was analyzed. Moreover, renal carcinoma Renca cells stably expressing C5aR were generated and used to assess the effects of C5a-C5aR axis activation on various cellular phenomena in culture. Immunohistochemistry revealed that 96.7% of the metastatic RCCs (mRCCs) showed C5aR expression, whereas only 50.5% of the non-metastatic RCCs expressed C5aR (P<0.001). Although C5a stimulation did not significantly alter anoikis of C5aR‑expressing Renca cells, C5a elicited cell morphological change and scattering of those cells accompanied with dynamic actin rearrangement, which was not observed in the Renca cells harboring the empty vector only. Moreover, C5a triggered ERK and PI3K‑dependent invasion of the C5aR-expressing renal carcinoma cells. These results are consistent with the idea that the C5a-C5aR axis plays a crucial role in renal carcinoma cell invasion, which may be one of the key steps for RCC metastasis. The present study provides proof‑of‑concept that the C5a-C5aR axis may be a useful therapeutic target for preventing RCC progression.
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Yoshihiro
authors: Y
authors: Maeda
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Yoshiaki
authors: Y
authors: Kawano
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Yoshihiro
authors: Y
authors: Wada
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Junji
authors: J
authors: Yatsuda
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Takanobu
authors: T
authors: Motoshima
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Yoji
authors: Y
authors: Murakami
authors: Medical Quality Management Center, Kumamoto University Hospital, Kumamoto 860-0811, Japan.
authors: Ken
authors: K
authors: Kikuchi
authors: Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors: Takahisa
authors: T
authors: Imamura
authors: Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
authors: Masatoshi
authors: M
authors: Eto
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D023102:Anoikis; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D015936:Complement C5a / Q000494:pharmacology / Q000502:physiology; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D044087:Receptor, Anaphylatoxin C5a / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000199:Actins; C488033:C5AR1 protein, human; C000591759:C5ar1 protein, mouse; D009363:Neoplasm Proteins; D044087:Receptor, Anaphylatoxin C5a; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D015936:Complement C5a; D019869:Phosphatidylinositol 3-Kinases