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C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2

Cancer Gene Therapy volume 28, pages 265–278 (2021)Cite this article

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A Correction to this article was published on 05 July 2021

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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.

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Fig. 1: C3a/C5a concentration in MM patients and the expression of C3a/C5a receptors on cells from MM patients.
Fig. 2: Effects of C3 and C5 cleavage fragments on the migration, invasion and adhesion of human MM cells.
Fig. 3: C3 and C5 cleavage fragments increased the expression of phosphorylated MEK1/MEK2 and upregulated the nuclear expression of Nrf2.
Fig. 4: Inhibition of MEK1/MEK2 or downregulation of Nrf2 suppresses invasion and adhesion of MM cells.
Fig. 5: C3 and C5 cleavage fragments facilitated the spread of human MM cells in vivo, while Nrf2 downregulation inhibited the metastasis of leukemic cells in vivo.
Fig. 6: Mechanism diagram.

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Acknowledgements

The authors thank Hematopoietic Stem Cell Laboratory of Guizhou Medical University for providing the clinical samples.

Funding

This study was supported by the grants from the National Natural Science Foundation of China (81960032,81960357,81701958) and Translational Research Grant of NCRCH (2020ZKPB03).

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Authors and Affiliations

  1. 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

    Jie Xiong & Depei Wu

  2. 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

    Jie Xiong, Xingyi Kuang, Tingting Lu, Kunlin Yu, Zhaoyuan Zhang, Weili Wang, Lu Zhao & Jishi Wang

  3. Department of Critical Care Medicine, The Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China

    Xu Liu

  4. Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, 550001, Guiyang, China

    Qin Fang

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Xiong, J., Kuang, X., Lu, T. et al. C3a and C5a facilitates the metastasis of myeloma cells by activating Nrf2. Cancer Gene Ther 28, 265–278 (2021). https://doi.org/10.1038/s41417-020-00217-0

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