SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes

Song, Xian‐Rong; Wan, Xuechao; Huang, Tianzhi; Zeng, Chang; Sastry, Namratha; Wu, Bing‐Li; James, C. David; Horbinski, Craig; Nakano, ﻿Ichiro; Zhang, Wei; Hu, Bo; Cheng, Shi Yuan

doi:10.1158/0008-5472.can-19-1504

Cited by 74 publications

(90 citation statements)

References 53 publications

(77 reference statements)

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“…The binding of hnRNPA1, hnRNPA2, and PTBP1 to sequences flanking exon 9 promotes the inclusion of exon 10 and expression of PKM2, thus ensuring high glycolytic flux in GBM cells [45,46]. Another splicing factor contributing to this metabolic switch is the SR protein SRSF3, which is also up-regulated in gliomas and sustains glioma stem cells (GSCs) growth, self-renewal, and tumorigenicity [47]. Whole transcriptome analysis revealed a role for SRSF3 as widespread modulator of gene expression and splicing in GBM ( Table 2).…”

Section: Splicing Dysregulation In Brain Tumorsmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology.

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Section: Splicing Dysregulation In Brain Tumorsmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

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“…Amiodarone's suppressive effects on the SRSF3 promoter activity were further veri ed in GBM8401 and U118MG glioma cell lines [6]. Numerous studies demonstrated that SRSF3 and miR-224 are frequently upregulated in glioma cells and are associated with tumor progression and a poor prognosis in glioma patients [32,33].…”

Section: Discussionmentioning

confidence: 98%

Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

Steinberg

Fluksman

Zemmour

et al. 2020

Preprint

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Background: Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. In this study, we examined Amiodarone's effects on glioblastoma multiforme (GBM), a highly aggressive and hypervascularized cancer. We hypothesized that Amiodarone would show an anti-angiogenic effect on GBM in addition to its previously suggested anti-cancer activity, and that an ultra-low dose would be both effective and possibly avert the drug’s side effects. Methods: The anti-cancer activity of Amiodarone was assessed by several in vitro assays using GBM cells. This included cytotoxicity, proliferation, transwell migration, Anoikis, colony-formation and three-dimensional (3D) spheroid growth assays. The anti-angiogenic effect of Amiodarone was tested on endothelial cells, using toxicity, proliferation, migration and tube formation in vitro assays. The anti-cancer and anti-angiogenic activity of Amiodarone was examined in vivo on three different murine models. C57BL/6J mice were utilized for the corneal neovascularization model and the Matrigel plug assay. Foxn1 nu mice were inoculated with GBM cells and used for the GBM tumor xenograft model.Results: In this study, we showed that Amiodarone has a significant anti-cancer and anti-angiogenic activity in vitro. Moreover, ultra-low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect in vivo. Conclusions: Our results strongly suggest that Amiodarone possess dual cancer fighting properties.

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“…Functional mutations of SRSF2 drive the cancer genesis of hematopoietic cells [43]. SRSF3 is a multiple cancer related splicing factor, namely glioblastoma [44], colon cancer [45], oral squamous carcinoma [46], etc. Moreover, the expression of SRSF2/3 is signi cantly decreased in de novo AML patients in comparison with that of healthy controls.…”

Section: Discussionmentioning

confidence: 99%

LINC00649 underexpression is an adverse prognostic marker in acute myeloid leukemia

Guo

Gao

et al. 2020

Preprint

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Background Long noncoding RNAs (lncRNA) play a role in leukemogenesis, maintenance, development, and therapeutic resistance of AML. While few studies have focused on the prognostic significance of LINC00649 in AML, which we aim to investigate in this present study. Methods We compared the expression level of LINC00649 between AML patients and healthy controls. The Kaplan-Meier curves of AML patients expressing high versus low level of LINC00649 was performed. The LINC00649 correlated genes/miRNAs/lncRNAs and methylation CpG sites were screened by Pearson correlation analysis with R (version 3.6.0), using TCGA-LAML database. The LINC00649 associated ceRNA network was established using lncBase 2.0 and miRWalk 2.0 online tools, combining results from correlation analysis. Finally, a prediction model was constructed using LASSO-Cox regression. Results LINC00649 was underexpressed in bone marrow of AML group than that in healthy control group. The patients of LINC00649-low group have significantly inferior PFS and OS. A total of 154 mRNAs, 31 miRNAs, 28 lncRNAs and 1590 methylated CpG sites were identified to be significantly correlated with LINC00649. Furthermore, the network of ceRNA was established with 6 miRNAs and 122 mRNAs. The Lasso-Cox model fitted OS/PFS to novel prediction models, which integrated clinical factors, ELN risk stratification, mRNA/miRNA expression and methylation profiles. The analysis of time-dependent ROC for our model showed a superior AUC (AUC = 0.916 at 1 year, AUC = 0.916 at 3 years, and AUC = 0.891 at 5 years). Conclusions Low expression of LINC00649 is a potential unfavorable prognostic marker for AML patients, which requires the further validation. The analysis by LASSO-COX regression identified a novel comprehensive model with a superior diagnostic utility, which integrated clinical and genetic variables.

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SRSF3-Regulated RNA Alternative Splicing Promotes Glioblastoma Tumorigenicity by Affecting Multiple Cellular Processes

Cited by 74 publications

References 53 publications

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

LINC00649 underexpression is an adverse prognostic marker in acute myeloid leukemia

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