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Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B
Xuexia Zhou, … , Qian Wang, Shizhu Yu
Xuexia Zhou, … , Qian Wang, Shizhu Yu
Published November 27, 2018
Citation Information: J Clin Invest. 2019;129(2):676-693. https://doi.org/10.1172/JCI120279.
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Research Article Cell biology Oncology

Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B

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Abstract

Abnormal alternative splicing (AS) caused by alterations to splicing factors contributes to tumor progression. Serine/arginine splicing factor 1 (SRSF1) has emerged as a key oncodriver in numerous solid tumors, leaving its roles and mechanisms largely obscure in glioma. Here, we demonstrate that SRSF1 is increased in glioma tissues and cell lines. Moreover, its expression was correlated positively with tumor grade and Ki-67 index, but inversely with patient survival. Using RNA-Seq, we comprehensively screened and identified multiple SRSF1-affected AS events. Motif analysis revealed a position-dependent modulation of AS by SRSF1 in glioma. Functionally, we verified that SRSF1 promoted cell proliferation, survival, and invasion by specifically switching the AS of the myosin IB (MYO1B) gene and facilitating the expression of the oncogenic and membrane-localized isoform, MYO1B-fl. Strikingly, MYO1B splicing was dysregulated in parallel with SRSF1 expression in gliomas and predicted the poor prognosis of the patients. Further investigation revealed that SRSF1-guided AS of the MYO1B gene increased the tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK pathways. Taken together, we identify SRSF1 as an important oncodriver that integrates AS control of MYO1B into promotion of gliomagenesis and represents a potential prognostic biomarker and target for glioma therapy.

Authors

Xuexia Zhou, Run Wang, Xuebing Li, Lin Yu, Dan Hua, Cuiyun Sun, Cuijuan Shi, Wenjun Luo, Chun Rao, Zhendong Jiang, Ying Feng, Qian Wang, Shizhu Yu

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Figure 9

AS of MYO1B is correlated with SRSF1 levels and predicts poor prognoses.

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AS of MYO1B is correlated with SRSF1 levels and predicts poor prognoses....
(A) Splicing pattern of MYO1B in glioma tissues as detected by RT-PCR (primer set 2). MYO1B-fl% is presented as mean ± SD, n = 3. (B) Pearson correlation analysis between SRSF1 mRNA levels and MYO1B-fl% in tissue samples (n = 19) as indicated in (A); r and P values by Pearson correlation test are presented. (C) Comparison of MYO1B-fl% between LGGs (n = 120) and GBMs (n = 120) using TCGA RNA-Seq data. ***P < 0.001 by 2-tailed Student’s t test. (D) Pearson correlation analysis between SRSF1 mRNA levels and MYO1B-fl% using the above TCGA data (n = 240). Pearson correlation test, r and P values are presented. (E) Kaplan-Meier analysis of the OS of the above patients in TCGA database. Patients were stratified into high and low expression subgroups using the median of MYO1B-fl% as the cutoff. P < 0.0001 by log-rank (Mantel-Cox) test.
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