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Multiple myeloma gammopathies

B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3

Leukemia volume 33, pages 1475–1486 (2019)Cite this article

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Abstract

B7-H3 (CD276) is broadly overexpressed by multiple human cancers. It plays a vital role in tumor progression and has been accepted as one of the inhibitory B7 family checkpoint molecules. To identify the functions and underlying mechanisms of B7-H3 in multiple myeloma, we analyzed B7-H3 expression in myeloma patients and used siRNAs and overexpression plasmid of B7-H3 to investigate its roles and downstream signaling molecules in myeloma cell lines. The results showed that surface expression of B7-H3 was upregulated in myeloma samples and cell lines. Lower expression of B7-H3 in myeloma cells was associated with better progression-free survival. Myeloma cell survival, drug resistance, and tumor growth could be promoted by B7-H3. The molecular basis for these functional roles of B7-H3 involved the activation of JAK2/STAT3 via redox-mediated oxidation and activation of Src. We further identified a STAT3-promoting signaling pathway by which oxidant-mediated Src phosphorylation led to secondary activation of the E3 ubiquitin ligase c-Cbl. Activated c-Cbl subsequently caused specific proteasomal degradation of SOCS3, a negative regulator of JAK2/STAT3. These data indicate B7-H3’s important role in the activation of ROS/Src/c-Cbl pathway in multiple myeloma which integrates redox regulation and sustained STAT3 activation at the level of degradation of STAT3 suppressor.

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Acknowledgements

The authors wish to thank Prof. Yingyu Chen, Yanhui Yin, Hongquan Zhang, and Genze Shao from Peking University Health Science Center for suggestions, critical comments, and reagents. The human myeloma cell lines NCI-H929 (shown as H929) and U266 were kindly provided by Prof. Jian Hou from Shanghai Chang Zheng Hospital and Prof. Yu Zhang from Peking University Health Science Center.

Funding

This work was supported by grants from the National Key Research and Development Program of China 2017YFA0104500, National Natural Science Foundation of China (31270935, 81471525, and 31671244, Q.G., 81670192, and YXJL-2017-0163-0006, J.L.), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (81621001, Q.G.) and the Fundamental Research Funds for the Central Universities.

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  1. These authors contributed equally: Liang Lin, Li Cao

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Peking University, 100191, Beijing, China

    Liang Lin, Li Cao, Ke Wang, Xinwei Zhang, Xiaodan Qin, Jie Hao, Jun Zhang & Qing Ge

  2. NHC Key Laboratory of Medical Immunology, Peking University, 100191, Beijing, China

    Liang Lin, Li Cao, Ke Wang, Xinwei Zhang, Xiaodan Qin, Jie Hao, Jun Zhang & Qing Ge

  3. Peking University Institute of Hematology, Collaborative Innovation Center of Hematology, People’s Hospital, 100044, Beijing, China

    Yang Liu, Yingjun Chang, Xiaojun Huang & Jin Lu

  4. Jining No.1 People’s Hospital, 6 Jiankang Road, 272011, Jining, Shandong, China

    Dandan Zhao

  5. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29466, USA

    Bei Liu

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Lin, L., Cao, L., Liu, Y. et al. B7-H3 promotes multiple myeloma cell survival and proliferation by ROS-dependent activation of Src/STAT3 and c-Cbl-mediated degradation of SOCS3. Leukemia 33, 1475–1486 (2019). https://doi.org/10.1038/s41375-018-0331-6

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