B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma

Jingwen Zhang, Jinhua Wang, Diego M. Marzese, Xiaowen Wang, Zixiao Yang, Chunjie Li, Haibo Zhang, Jinsen Zhang, Clark C Chen, Daniel F. Kelly, Wei Hua, Dave S.B. Hoon, Ying Mao

Research output: Contribution to journalArticle

Abstract

B7H3 (CD276), a co-stimulator molecule of the cell surface B7 protein superfamily, is expressed on glioblastomas (GBM). Recently, B7H3 functions beyond immune costimulation have been demonstrated. However, the mechanisms underlying B7H3 function are diverse and not well understood. GBM tumors contain undifferentiated self-renewing cells, which confound therapeutic attempts. We investigated the role of B7H3 in the regulation of GBM cell differentiation and the regulatory pathways involved. Analysis of public databases (TCGA, Rembrandt, and GEO NCBI) and RNA sequencing were performed to explore the role of B7H3 in GBM. Knockdown and overexpression of B7H3, were used to verify the downstream pathway in vitro. Further studies in vivo were performed to support the new finding. Bioinformatics analysis identified a correlation between the expression of B7H3, the expression of glioma self-renewing cell (GSC)-related genes, and MYC expression. These observations were verified by RNA-sequencing analyses in primary GBM cell lines. In vitro knockdown of B7H3-induced differentiation, associated with downregulation of SMAD6 (a TGF-β pathway inhibitor) and enhancement of SMAD1 phosphorylation-induced SMAD4 expression. Importantly, activation of the TGF-β pathway resulted in downregulation of MYC expression. In vivo assays conducted in a human GBM cell line xenograft mouse model demonstrated that B7H3 knockdown decreased MYC expression and inhibited tumor growth. B7H3 knockdown could regulate GBM differentiation by modulating MYC expression. So, B7H3 could serve as a potential theranostic target for the treatment of patients with GBM.

Original languageEnglish (US)
Pages (from-to)1117-1129
Number of pages13
JournalLaboratory Investigation
Volume99
Issue number8
DOIs
StatePublished - Jul 1 2019

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Glioblastoma
Biomarkers
RNA Sequence Analysis
Down-Regulation
Cell Line
Theranostic Nanomedicine
Computational Biology
Heterografts
Glioma
Cell Differentiation
Neoplasms
Membrane Proteins
Phosphorylation
Databases
Gene Expression
Therapeutics
Growth

PubMed: MeSH publication types

  • Journal Article

Cite this

B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma. / Zhang, Jingwen; Wang, Jinhua; Marzese, Diego M.; Wang, Xiaowen; Yang, Zixiao; Li, Chunjie; Zhang, Haibo; Zhang, Jinsen; Chen, Clark C; Kelly, Daniel F.; Hua, Wei; Hoon, Dave S.B.; Mao, Ying.

In: Laboratory Investigation, Vol. 99, No. 8, 01.07.2019, p. 1117-1129.

Research output: Contribution to journalArticle

Zhang, J, Wang, J, Marzese, DM, Wang, X, Yang, Z, Li, C, Zhang, H, Zhang, J, Chen, CC, Kelly, DF, Hua, W, Hoon, DSB & Mao, Y 2019, 'B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma', Laboratory Investigation, vol. 99, no. 8, pp. 1117-1129. https://doi.org/10.1038/s41374-019-0238-5
Zhang, Jingwen ; Wang, Jinhua ; Marzese, Diego M. ; Wang, Xiaowen ; Yang, Zixiao ; Li, Chunjie ; Zhang, Haibo ; Zhang, Jinsen ; Chen, Clark C ; Kelly, Daniel F. ; Hua, Wei ; Hoon, Dave S.B. ; Mao, Ying. / B7H3 regulates differentiation and serves as a potential biomarker and theranostic target for human glioblastoma. In: Laboratory Investigation. 2019 ; Vol. 99, No. 8. pp. 1117-1129.
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