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

Hanqing Chen,Qinghua Bao,Jun Dong,Xueguang Zhang,Fengqing Fu,Yundi Guo,Jing Sun

doi:10.1155/2020/2328675

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.

Highlights

Malignant gliomas are the most common type of primary malignant brain tumor, according for approximate 80% of patients
The data show B7 homologue 6 (B7-H6) expresses on glioma tissues but not on cell lines, suggesting that it might express in cancer stem cells
We have revealed that the B7-H6, a newly identified molecule of the B7 family [14], was abnormally expressed in human glioma tissues and enhanced tumor cell proliferation

Summary

Introduction

Malignant gliomas are the most common type of primary malignant brain tumor, according for approximate 80% of patients. Singh et al isolated tumor initial cells by sorting stem cell marker CD133-positive cells [6], while Ignatova et al and Galli et al identified glioma stem-like cells from tumor samples based on neurosphere formation ability in vitro [7, 8]. They showed that the isolated cells to be self-renewing and radiotherapy- and chemotherapy-resistant [9]. The key molecules and mechanisms underlying tumor stemness remain largely unknown

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