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Immunoregulatory protein B7-H3 regulates cancer stem cell enrichment and drug resistance through MVP-mediated MEK activation

Oncogene (2018) | Download Citation

Abstract

B7-H3 is a tumor-promoting glycoprotein that is expressed at low levels in most normal tissues, but is overexpressed in various human cancers which is associated with disease progression and poor patient outcome. Although numerous publications have reported the correlation between B7-H3 and cancer progression in many types of cancers, mechanistic studies on how B7-H3 regulates cancer malignancy are rare, and the mechanisms underlying the role of B7-H3 in drug resistance are almost unknown. Here we report a novel finding that upregulation of B7-H3 increases the breast cancer stem cell population and promotes cancer development. Depletion of B7-H3 in breast cancer significantly inhibits the cancer stem cells. By immunoprecipitation and mass spectrometry, we found that B7-H3 is associated with the major vault protein (MVP) and activates MEK through MVP-enhancing B-RAF and MEK interaction. B7-H3 expression increases stem cell population by binding to MVP which regulates the activation of the MAPK kinase pathway. Depletion of MVP blocks the activation of MEK induced by B7-H3 and dramatically inhibits B7-H3 induced stem cells. This study reports novel functions of B7-H3 in regulating breast cancer stem cell enrichment. The novel mechanism for B7-H3-induced stem cell propagation by regulating MVP/MEK signaling axis independent of the classic Ras pathway may have important implications in the development of strategies for overcoming cancer cell resistance to chemotherapy.

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Acknowledgements

This study was supported by NIH grants R01CA149646 (to M. Tan), the Vincent F. Kilborn, Jr. Cancer Research Foundation (to MT). NIH CA148629 to RWS. RWS is an Abraham A. Mitchell Distinguished Investigator.

Author information

Affiliations

  1. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

    • Zixing Liu
    • , Joshua B. Phillips
    • , Ritu Arora
    • , Steven McClellan
    • , Jiangfeng Li
    • , Jin-Hwan Kim
    • , Robert W. Sobol
    •  & Ming Tan
  2. Department of Medical Laboratory Science, Xiangya School of Medicine, Central South University, Changsha, China

    • Wenling Zhang
  3. Department of Biochemistry and Molecular Biology, University of South Alabama, 307N. University Blvd, Mobile, AL, 36688, USA

    • Ming Tan

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The authors declare that they have no conflict of interest.

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Correspondence to Ming Tan.

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DOI

https://doi.org/10.1038/s41388-018-0407-9