Germ Cell-Specific Gene 1-Like Protein Regulated by Splicing Factor CUGBP Elav-Like Family Member 5 and Primary Bile Acid Biosynthesis are Prognostic in Glioblastoma Multiforme

Runzhi Huang; Zhenyu Li; Chen Li; Guanghua Wang; Penghui Yan; Li Peng; Jiaqi Wang; Xiaolong Zhu; Peng Hu; Junfang Zhang; Zhengyan Chang; Zongqiang Huang; Liming Cheng; Jie Zhang

doi:10.3389/fgene.2019.01380

Germ Cell-Specific Gene 1-Like Protein Regulated by Splicing Factor CUGBP Elav-Like Family Member 5 and Primary Bile Acid Biosynthesis are Prognostic in Glioblastoma Multiforme

Front Genet. 2020 Feb 4:10:1380. doi: 10.3389/fgene.2019.01380. eCollection 2019.

Authors

Runzhi Huang^{1

2}, Zhenyu Li^{1

3}, Chen Li², Guanghua Wang¹, Penghui Yan⁴, Li Peng⁵, Jiaqi Wang^{1

3}, Xiaolong Zhu⁴, Peng Hu⁴, Junfang Zhang^{1

3}, Zhengyan Chang⁶, Zongqiang Huang⁴, Liming Cheng², Jie Zhang^{1

3}

Affiliations

¹ Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
² Division of Spine, Department of Orthopedics, Tongji Hospital affiliated to Tongji University School of Medicine, Shanghai, China.
³ Tongji University School of Medicine, Shanghai, China.
⁴ Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁵ Shanghai Key Laboratory of Meteorology and Health, Shanghai, China.
⁶ Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

Background: Alternative splicing (AS) modifies 92-94% human genes, abnormal splicing events might relate to tumor development and invasion. Glioblastoma Multiforme (GBM) is a fatal, invasive, and malignant tumor in nervous system. The recurrence and development leads to poor prognosis. However, few studies have focused on AS in GBM.

Methods: RNA-seq and Alternative splicing events (ASEs) data of GBM samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, respectively. Firstly, the Cox regression analysis was utilized to identify the overall survival splicing events (OS-SEs). Secondly, a multivariable model was applied to access the prognostic value of risk score. Then, we constructed a co-expressed network between splicing factors (SFs) and overall survival alternative splicing events (OS-SEs). Additionally, to explore the relationship between the potential prognostic signaling pathways and OS-SEs, we constructed a network between these pathways and OS-SEs. Ultimately, to better explain the results, validations from multi-dimension platforms were applied.

Results: In the first step, 1,062 OS-SEs were selected by Cox regression. Then, 11 OS-SEs were integrated in a multivariate model by Lasso regression. The area under the curve (AUC) of receiver operator characteristic (ROC) curve was 0.861. In addition, the risk score generated from the multivariate model was confirmed to be an independent prognostic factor (P < 0.001). What's more, in the network of SFs and ASEs, CELF5 significantly regulated GSG1L|35696|AP and GSG1L|35698|AP (P < 0.001, R = 0.511 and = -0.492). Additionally, GSG1L|35696|AP (P = 0.006) and GSG1L|35698|AP (P = 0.007) showed a significant relationship with cancer status. Eventually, KEGG pathways related to prognosis of GBM were selected by GSVA. The primary bile acid synthesis (P < 0.001, R = 0.420) was the significant pathway co-expressed with Germ Cell-Specific Gene 1-Like Protein (GSG1L).

Conclusions: Based on the comprehensive bioinformatics analysis, we proposed that aberrant splicing factor CUGBP Elav-like family member 5 (CELF5) significantly, positively and negatively, regulated ASE of GSG1L, and the primary bile acid synthesis pathway might play an important role in tumorigenesis and prognosis of GBM.

Keywords: alternative splicing; glioblastoma multiforme; pathway; prognosis; splicing factor.