C5a stimulates the proliferation of breast cancer cells via Akt-dependent RGC-32 gene activation

Abstract

Complement system activation contributes to various immune and inflammatory diseases, as well as cancers.However, the role of complement activation in the proliferation of cancer cells is not clear. In the present study, we investigated the consequences of complement activation on the proliferation of breast cancer cells and its possible mechanisms. We focused our study on the potential roles of the anaphylatoxins C3a and C5a in the proliferation of human breast cancer, as two important immune mediators generated after complement activation. Our study revealed that C5a stimulation, but not C3a, enhanced the proliferation of human breast cancer cells in vitro. Moreover, the expression of response gene to complement 32 (RGC-32) was pronounced in breast cancer cells in response to C5a stimulation. Notably, blockade of the C5a receptor markedly reduced the expression of RGC-32 and the proliferation of breast cancer cells stimulated by C5a. Meanwhile, silencing of RGC-32 expression reduced the proliferation of breast cancer cells induced by C5a treatment. Further investigation revealed that Akt activation was involved in C5a-induced RGC-32 expression and breast cancer cell proliferation. In conclusion, the present study indicates that C5a may promote the proliferation of breast cancer cells through Akt1 activation of the RGC-32 gene.

Expression of RGC32 in human normal and preeclamptic placentas and its role in trophoblast cell invasion and migration

“…4). Recently, some studies have reported that Akt activation participated in C5a-induced RGC32 expression in breast cancer cells [30] and hyperglycemia-or hyperinsulinemia-induced RGC32 expression in endothelial cells [31]. Meanwhile, other studies have shown that RGC32 silencing inhibited C5b-9-mediated Akt phosphorylation in human aortic vascular endothelial cells [32].…”

Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

“…C5aR1 is expressed in many cells, including in lung alveolar and airway epithelium as well as the endothelium (27, 28). C5aR1‐mediated divergent signaling leads either to apoptosis or cell survival, via ERK (29), Akt activation (30), PKC‐mediated IL‐8 release by the airway epithelium (31), or fibrosis in other organs (32, 33) compared with C5aR2, which is implicated in acute inflammation (34, 35) and balances the biologic responses to C5a (36, 37). Whereas the pathogenesis of acute lung injury has been associated with the destructive effects of C3aR‐dependent (38) and C5aR‐dependent signaling (5, 38, 39) and with the extracellular histone‐dependent signaling of C5aR1/2 (35), the protective effects due to the blockade of C3aR and C5aR1 in airway hyper‐responsiveness and inflammation (40) as well as in renal injury/fibrosis are known (33, 41).…”

RGC32 induces epithelial-mesenchymal transition by activating the Smad/Sip1 signaling pathway in CRC

“…in 19983. It plays important roles in the regulation of cell differentiation, angiogenesis, migration, and invasion456. In addition, emerging evidence has revealed that RGC32 is involved in lung cancer7, breast cancer8, hepatic steatosis9, and multiple sclerosis10.…”