Dataset Information

Preferential Expression of B7-H6 in Glioma Stem-Like Cells Enhances Tumor Cell Proliferation via the c-Myc/RNMT Axis.

ABSTRACT: B7 homologue 6 (B7-H6), a newly identified member of the B7 costimulatory molecule family, is not only a crucial regulator of NK cell-mediated immune responses through binding to NKp30 but also has clinical implications due to its abnormal expression in human cancers. Here, we show that B7-H6 expression is abnormally upregulated in glioma tissue and that B7-H6 is coexpressed with stem cell marker Sox2. Intriguingly, B7-H6 was rarely detected on the surface of glioma cell lines but was abundantly expressed in glioma stem-like cells (GSLCs) that were derived from the glioma cell lines in vitro. Surprisingly, B7-H6 was the only one that was preferentially expressed in the GSLCs among the B7 family members. Functionally, knockdown of B7-H6 in GSLCs by siRNAs led to the inhibition of cell proliferation, with decrease in the expression of the oncogene Myc as well as inactivation of PI3K/Akt and ERK/MAPK signaling pathways. Moreover, we determined that three genes CBL (Casitas B-Lineage Lymphoma Proto-Oncogene), CCNT1 (Cyclin T1), and RNMT (RNA guanine-7 methyltransferase) were coexpressed with B7-H6 and c-myc in glioma tissue samples from the TCGA database and found, however that only RNMT expression was inhibited by the knockdown of B7-H6 expression in the GSLCs, suggesting the involvement of RNMT in the B7-H6/c-myc axis. Extending this to 293T cells, we observed that knocking out of B7-H6 with CRISPR-Cas9 system also suppressed cell proliferation. Thus, our findings suggest B7-H6 as a potential molecule for glioma stem cell targeted immunotherapy.

SUBMITTER: Chen H

PROVIDER: S-EPMC7165331 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Preferential Expression of B7-H6 in Glioma Stem-Like Cells Enhances Tumor Cell Proliferation via the c-Myc/RNMT Axis.

Chen Hanqing H Guo Yundi Y Sun Jing J Dong Jun J Bao Qinghua Q Zhang Xueguang X Fu Fengqing F

Journal of immunology research 20200406

B7 homologue 6 (B7-H6), a newly identified member of the B7 costimulatory molecule family, is not only a crucial regulator of NK cell-mediated immune responses through binding to NKp30 but also has clinical implications due to its abnormal expression in human cancers. Here, we show that B7-H6 expression is abnormally upregulated in glioma tissue and that B7-H6 is coexpressed with stem cell marker Sox2. Intriguingly, B7-H6 was rarely detected on the surface of glioma cell lines but was abundantly ...[more]

PMID: 32322592

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Project description:Purpose:B7 homologue 6 (B7-H6) has been found at an up-regulated level in multiple cancer cells and identified to be positively correlated with inferior clinical features. In non-Hodgkin lymphoma (NHL), however, the roles of B7-H6 and the underlying mechanism of action remain unclear. Through in vivo and in vitro experiments, the aim of this study was to explore the regulatory mechanism of B7-H6 in NHL in order to provide new therapeutic strategies that can potentially be applied in clinical practice. Methods:The expression of B7-H6 in T-lymphoblastic lymphoma (TLBL), diffuse large B cell lymphoma (DLBCL) and lymph node reactive hyperplasia (LRH) tissues were compared by immunohistochemistry. A total of 10 NHL cell lines were screened by Western blot to evaluate the expression of B7-H6. The effects of B7-H6 knockdown on cell proliferation, migration and invasion of NHL cells were studied in vivo using a transplanted tumor mice model, and in vitro by Cell Counting Kit-8 (CCK-8) and Transwell assays. Quantitative phosphoproteomics was performed to identify the changes of protein phosphorylation and related pathways affected by B7-H6. The effects of B7-H6 on NHL were validated via B7-H6 overexpression and pathway inhibitor assays. Results:The expression levels of B7-H6 in NHL cell lines, and TLBL and DLBCL tissues were significantly increased compared with those in the control groups. Inhibition of cell proliferation, migration and invasion was observed in Jurkat and Raji cells with B7-H6 knockdown. The ability of B7-H6 in promoting tumorigenesis was further validated by in vivo experiments. In addition, Ras and HIF-1 signaling pathways were shown to be significantly affected by B7-H6 through quantitative phosphorylation proteomics analysis. Ras/MEK/ERK pathway was verified to be significantly inhibited after B7-H6 knockdown by Western blot analysis. Strikingly, MEK inhibitor AZD8330 was found to have the ability to sufficiently inhibit Ras/MEK/ERK pathway, partially reverse cell proliferation and completely reverse cell migration and invasion induced by B7-H6. Conclusion:B7-H6 promotes cell proliferation, migration and invasion in NHL via Ras/MEK/ERK pathway. Hence, B7-H6 or Ras/MEK/ERK pathway targeting may be used as potential therapeutics for treating NHL.

Dataset Information

Preferential Expression of B7-H6 in Glioma Stem-Like Cells Enhances Tumor Cell Proliferation via the c-Myc/RNMT Axis.

Publications

Preferential Expression of B7-H6 in Glioma Stem-Like Cells Enhances Tumor Cell Proliferation via the c-Myc/RNMT Axis.

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