A novel functional polymorphism of GFAP decrease glioblastoma susceptibility through inhibiting the binding of miR-139

Abstract

Glioblastoma (GBM) is the most commonly diagnosed solid tumor outside the central nervous system. However, genetic factors underlying GBM remain largely unclear. Previous studies indicated that Glial fibrillary acidic protein (GFAP) might play an important role in the aggressiveness of GBM and also contributed to its poor overall survival. The present study aims to test (1) the associations between GFAP single nucleotide polymorphisms (SNPs) and GBM cells chemoresistance and metastasis, and (2) the molecular mechanism accounting for their effects. Four tagging SNPs of GFAP were initially genotyped in 667 subjects and the significant SNP was further analyzed via online bioinformatical tools. SNP rs11558961 was found to be significantly associated with GBM susceptibility. It was predicted to influence microRNA(miR)-139 binding to 3'UTR of GFAP gene. In functional experiments, we found that cells transfected with rs11558961 G-allele constructs had lower baseline luciferase activities and were more responsive to miR-139 changes, compared to C-allele constructs. Moreover, rs11558961 C>G variant reduced the chemoresistance of GBM cells and migration capability. In conclusion, rs11558961 might influence the chemoresistance and progression of GBM cells via promoting the binding of miR-139, ultimately decrease the susceptibility of GBM. This investigation will shed light on the optimizing for clinical trial design and individualizing of therapeutic plans.

Inhibition of microRNA-103a inhibits the activation of astrocytes in hippocampus tissues and improves the pathological injury of neurons of epilepsy rats by regulating BDNF

“…A growing number of evidences revealed that GFAP level increased in high-grade brain tumors, implying the important role of GFAP in the aggressiveness of brain tumors [41–43]. It is reported that via interfering the binding of miR-139 and 3′UTR, variant G allele of rs11558961 that reduced GFAP expression contributes to low GFAP expression, and further inhibits the chemo-resistance and metastasis of glioblastoma (GBM) cells [44]. Additionally, the results of our study suggested that inhibiting miR-103a expression can attenuate injury of hippocampal neurons in epilepsy rats, which is reflected by the results that the mRNA expression of IL-6 and TNF-α decreased significantly in the hippocampus tissues of rats in the EP + miR-103a inhibitors group.…”

Regulation of GFAP Expression

“…Involvement of another miRNA, miR-139, was pursued by Wang J et al (2018). In a search for SNPs associated with risk for glioblastoma, they identified a C/G polymorphism in the 3'UTR of GFAPa at þ8182.…”

Identification of robust diagnostic and prognostic gene signatures in different grades of gliomas: a retrospective study

“…Relevant teams analyzed the glioma data obtained from TCGA and verified the expression of differential proteins in the tissues or body fluids of glioma patients, animal models and cell lines. Common targets are GFAP ( Wang et al, 2018 ), HSP70 ( Sharifzad et al, 2020 ), VEGF ( Nicolas et al, 2019 ), BDNF ( Huo & Chen, 2019 ), ECM ( Tejero et al, 2019 ), FN1 ( Yu et al, 2020 ; Gu, Gu & Shou, 2014 ; Guo, Heller & Thorslund, 2016 ; Liao et al, 2018 ), CD44 ( Mooney et al, 2016 ), Fransgelin-2, Short Hairpin RNAGLN and GRN ( Ness, Riemenschneider & Baches., 2009 ; Trigos et al, 2019 ) etc. Previous research suggested that TAGLN2 might be involved in progression due to its higher expression in glioblastomas compared to IDH1/2 WT gliomas of lower grades ( Beyer et al, 2018 ; Han et al, 2017 ).…”