C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2
Authors: Jishi Wang
Lu Zhao
Jie Xiong
Kunlin Yu
Qin Fang
Zhaoyuan Zhang
Weili Wang
Depei Wu
Tingting Lu
Xu Liu
Xingyi Kuang
Journal: Cancer Gene Therapy (2020)
Discipline: CLINICAL MEDICINE
Keywords: Multiple myeloma; C3a; C5a; migration; invasion
Affiliations: Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China., Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China., Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China., Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China., Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis under Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou Institute of Blood and Marrow Transplantation, 188 Shizi Street, 215006, Suzhou, Jiangsu, China. ., Department of Hematology, The Affiliated Hospital of Guizhou Medical University. Hematopoietic Stem Cell Transplantation Center of Guizhou Province, Key Laboratory of Hematological Disease Diagnostic & Treat Centre of Guizhou Province. Guizhou Medical University, 550001, Guiyang, China. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 In Figure 4 I,J, a loading control (beta-actin) has been reused (U266 vs RPMI8226). ![file] ,