Immunoregulatory protein B7-H3 regulates cancer stem cell enrichment and drug resistance through MVP-mediated MEK activation.
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.
Mesh Terms:
Animals, B7 Antigens, Breast Neoplasms, Butadienes, CRISPR-Cas Systems, Cell Line, Tumor, Cell Polarity, Drug Resistance, Neoplasm, Enzyme Activation, Female, Humans, MAP Kinase Kinase Kinases, Mice, Mice, Nude, Nanog Homeobox Protein, Neoplasm Invasiveness, Neoplasm Proteins, Neoplastic Stem Cells, Nitriles, Protein Domains, Protein Interaction Mapping, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, RNA Interference, RNA, Guide, RNA, Small Interfering, Recombinant Proteins, SOXB1 Transcription Factors, Sequence Deletion, Spheroids, Cellular, Transfection, Up-Regulation, Vault Ribonucleoprotein Particles
Animals, B7 Antigens, Breast Neoplasms, Butadienes, CRISPR-Cas Systems, Cell Line, Tumor, Cell Polarity, Drug Resistance, Neoplasm, Enzyme Activation, Female, Humans, MAP Kinase Kinase Kinases, Mice, Mice, Nude, Nanog Homeobox Protein, Neoplasm Invasiveness, Neoplasm Proteins, Neoplastic Stem Cells, Nitriles, Protein Domains, Protein Interaction Mapping, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, RNA Interference, RNA, Guide, RNA, Small Interfering, Recombinant Proteins, SOXB1 Transcription Factors, Sequence Deletion, Spheroids, Cellular, Transfection, Up-Regulation, Vault Ribonucleoprotein Particles
Oncogene
Date: Dec. 01, 2018
PubMed ID: 30082909
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