Department of Urology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860‑8556, Japan.
Medical Quality Management Center, Kumamoto University Hospital, Kumamoto 860-0811, Japan.
Oncol Rep. 2015 Apr;33(4):1844-50. doi: 10.3892/or.2015.3800. Epub 2015 Feb 13.
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.
过敏毒素 C5a 通过 C5a 受体 (C5aR) 作为白细胞迁移的趋化因子。我们最近报道 C5aR 在多种人类相关癌症中异常表达，而 C5a 刺激也通过促进癌细胞侵袭来促进癌症进展。然而，C5aR 在肾细胞癌 (RCC) 中的表达的生物学意义尚未阐明。在本研究中，我们旨在阐明 C5aR 在 RCC 进展中的生物学作用。分析了临床 RCC 标本中 C5aR 的表达情况，并分析了其与基线人口统计学数据和临床病理参数的关系。此外，还生成了稳定表达 C5aR 的肾癌细胞系 Renca 细胞，并用于评估 C5a-C5aR 轴激活对培养中各种细胞现象的影响。免疫组织化学显示，96.7%的转移性 RCC (mRCC) 显示 C5aR 表达，而只有 50.5%的非转移性 RCC 表达 C5aR (P<0.001)。虽然 C5a 刺激并没有显著改变表达 C5aR 的 Renca 细胞的凋亡，但 C5a 引起了细胞形态的变化和这些细胞的散射，伴随着动态肌动蛋白重排，而仅携带空载体的 Renca 细胞则没有观察到这种情况。此外，C5a 触发了表达 C5aR 的肾癌细胞的 ERK 和 PI3K 依赖性侵袭。这些结果与 C5a-C5aR 轴在肾癌细胞侵袭中发挥关键作用的观点一致，这可能是 RCC 转移的关键步骤之一。本研究提供了概念验证，即 C5a-C5aR 轴可能是预防 RCC 进展的一个有前途的治疗靶点。
