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

Date Published: May 10, 2018

Publisher: Impact Journals

Author(s): Jie Wang, Ming-Lei Wang, Chang-Hui Wang, Shu-Yan Sun, Han-Bing Zhang, Yang-Yang Jiang, Qi-Wu Xu, Ying Wang, Shi-Xin Gu.

http://doi.org/10.18632/aging.101442

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.

Partial Text

Glioblastoma (GBM) is the most fatal brain tumor and only a few prognostic factors such as age, initial Karnofsky performance status are known [1]. After diagnosis, the median survival of GBM is approximately 14 months [2] and GBM exhibits a high chemoresistance [3]. Therefore, identification and characterization of the role of genetic variations in predicting GBM risk are very important. It may help optimize clinical trial design and individualize therapeutic plans.

In the present study, we investigated the genetic effects of SNPs in GFAP gene on the progression of GBM. Four candidate SNPs were genotyped using MALDI-TOF MS in 261 patients and 406 healthy controls. A significant association between rs11558961 and decreased GBM susceptibility was identified. Variant G allele of rs11558961 reduced GFAP expression via interfering the binding of miR-139 and 3’UTR, resulting in low GFAP expression level, and further suppressing the chemoresistance and metastasis of GBM cells (Fig. 6).

 

Source:

http://doi.org/10.18632/aging.101442

 

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