Multiple myeloma (MM) is still an incurable hematological malignancy, with even poorer prognosis in MM patients with distant invasion. The present study was designed to explore the effects of C3a and C5a on the migration, invasion, and adhesion of MM tumor cells and to investigate the underlying mechanisms. As a result, the levels of C3a and C5a in plasma of MM patients were significantly higher than those of healthy donors. Consistently, the expression of C3a and C5a receptors on myeloma cells of MM patients was also significantly higher than that on sorted plasma cells of normal donors. C3a and C5a have been confirmed to increase the migration, invasion and adhesion of MM cell lines by activating the MEK/ERK pathway and increasing the nuclear transfer of Nrf2 in vitro. Moreover, the MM cell line U266 with Nrf2 downregulation was incubated with C3a and C5a, followed by injection into the tail vein of NOD-SCID mice. We found that Nrf2 downregulation attenuated the migration of anaphylatoxin C3a and C5a to MM tumor cells in bone marrow, liver and lung in vivo. In conclusion, our results indicate that activation of the complement cascade in MM patients may contribute to the migration, invasion and adhesion of MM cells, and this type of tumor cells dissemination in MM is, at least partially, regulated by Nrf2. Thereby, complement suppression or Nrf2 downregulation might offer a novel therapeutic opportunity for MM.

多发性骨髓瘤（MM）仍然是一种无法治愈的血液恶性肿瘤，远处侵袭的MM患者预后更差。本研究旨在探讨C3a和C5a对MM肿瘤细胞迁移、侵袭和粘附的影响并探讨其潜在机制。结果，MM患者血浆中C3a和C5a的水平显着高于健康供者。一致的是，MM患者的骨髓瘤细胞上C3a和C5a受体的表达也显着高于正常供体的分选浆细胞。C3a和C5a已被证实在体外通过激活MEK/ERK通路和增加Nrf2的核转移来增加MM细胞系的迁移、侵袭和粘附。此外，将Nrf2下调的MM细胞系U266与C3a和C5a一起孵育，然后注射到NOD-SCID小鼠的尾静脉中。我们发现 Nrf2 下调可减弱体内过敏毒素 C3a 和 C5a 向骨髓、肝脏和肺中 MM 肿瘤细胞的迁移。总之，我们的结果表明，MM患者中补体级联的激活可能有助于MM细胞的迁移、侵袭和粘附，并且MM中的此类肿瘤细胞传播至少部分地受到Nrf2的调节。因此，补体抑制或 Nrf2 下调可能为 MM 提供新的治疗机会。