Zheng Jing-Min, Zhou Han-Xi, Yu Hong-Yuan, Xia Yu-Hui, Yu Qing-Xin, Qu Hang-Shuai, Bao Jia-Qian
Department of Urology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China.
Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China.
Cancer Manag Res. 2021 Oct 4;13:7607-7621. doi: 10.2147/CMAR.S326352. eCollection 2021.
Contradictive results about the direct role of C5a/C5aR1 axis in different cancer cells have been reported. The direct effect of C5a on human renal cell carcinoma (RCC) cells and the underlying mechanism are not clear. The aim of this study is to investigate the role of C5a/C5aR1 axis in RCC cells and its working mechanism.
RCC cells were infected with lentivirus Lenti-C5a, which was designed to over-express secretory C5a in the cells, or directly treated with recombinant C5a, the influence of these treatments in the cells and the underlying mechanism were explored.
Transfection of RCC cells with Lenti-C5a markedly increased the production of C5a and significantly increased the proliferation, migration, and invasion of RCC cells, but direct addition of C5a to the cell culture medium had no such effects though it indeed induced a transient intracellular calcium rise. RCC cells were found to express carboxypeptidase D and M, which reportedly to inactivate C5a. Also, the RCC cells stably transfected with Lenti-C5a produced larger transgrafted tumors in nude mice compared with the non-transfected or control virus transfected cells. In addition, over-expression of C5a significantly increased the expression and phosphorylation of STAT3 as well as the phosphorylated JNK level. Furthermore, the effect of C5a over-expression on RCC cells' proliferation, migration, and invasion could be blocked by Stattic, a STAT3-specific inhibitor.
Chronic over-activation of C5a/C5aR1 axis could directly increase RCC cells' proliferation, migration, and invasion and thus contribute directly to the progression of the disease. Over-activation of STAT3 pathway is among the underlying mechanism.
关于C5a/C5aR1轴在不同癌细胞中的直接作用，已有相互矛盾的研究结果报道。C5a对人肾细胞癌（RCC）细胞的直接作用及其潜在机制尚不清楚。本研究旨在探讨C5a/C5aR1轴在RCC细胞中的作用及其作用机制。
用慢病毒Lenti-C5a感染RCC细胞，该慢病毒旨在使细胞中分泌性C5a过表达，或直接用重组C5a处理，探讨这些处理对细胞的影响及其潜在机制。
用Lenti-C5a转染RCC细胞可显著增加C5a的产生，并显著增加RCC细胞的增殖、迁移和侵袭能力，但直接向细胞培养基中添加C5a虽确实可诱导细胞内钙的短暂升高，但无上述作用。发现RCC细胞表达羧肽酶D和M，据报道这两种酶可使C5a失活。此外，与未转染或转染对照病毒的细胞相比，稳定转染Lenti-C5a的RCC细胞在裸鼠中产生的移植瘤更大。此外，C5a的过表达显著增加了STAT3的表达和磷酸化以及JNK的磷酸化水平。此外，STAT3特异性抑制剂Stattic可阻断C5a过表达对RCC细胞增殖、迁移和侵袭的影响。
C5a/C5aR1轴的慢性过度激活可直接增加RCC细胞的增殖、迁移和侵袭，从而直接促进疾病进展。STAT3通路的过度激活是其潜在机制之一。
