Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression

Shao, Ying; Chong, Wei; Liu, Xiaoli; Xu, Yitong; Zhang, Huikun; Xu, Qiao; Guo, Zhifang; Zhao, Yawen; Zhang, Ming; Ma, Yihui; Gu, Feng

doi:10.1038/s41419-019-1668-0

Cited by 25 publications

(33 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression of ITSN1-L was negatively correlated with brain tumor grade and prognosis in glioma. By contrast, expression of ITSN1-S was elevated in glioma [90]. Notably, while these isoforms did not shown differences in promoting cell growth, only ITSN1-L was capable to inhibit cell migration and invasion by affecting HDAC6-mediated stability of microtubules.…”

Section: Tumor Microenvironmentmentioning

confidence: 81%

“…Notably, while these isoforms did not shown differences in promoting cell growth, only ITSN1-L was capable to inhibit cell migration and invasion by affecting HDAC6-mediated stability of microtubules. Moreover, ITSN1-L was shown to attenuate cell-substrate adhesion and strengthen cell-cell junctions [90] (Table 2). These results suggest that a splicing switch from ITSN1-L to ITSN1-S favors glioma progression by modulating pro-invasion features.…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

See 1 more Smart Citation

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

View full text Add to dashboard Cite

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.

show abstract

Section: Tumor Microenvironmentmentioning

confidence: 81%

Section: Tumor Microenvironmentmentioning

confidence: 99%

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Bielli

Pagliarini

Pieraccioli

et al. 2019

Cells

View full text Add to dashboard Cite

show abstract

“…Studies suggest that apoptotic cell-derived extracellular vesicles promote GBM malignancy by mediating the intracellular transfer of splicing factors [23]. AS contributes to the variability of isoforms, which may play different roles in the progression of GBM [24,25]. Therefore, it is of great importance to elucidate the ambiguous functions of AS events and to determine the levels of splicing factors in GBM.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Profiling and Clinical Significance of Alternative Splicing Events in Glioblastoma

Ren

Liu

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Aims: The purpose of this study was to depict alternative splicing (AS) profiles in GBM and identify their clinical significance in the progression of GBM. Materials and Methods: RNA sequence data and clinical information were downloaded from The Cancer Genome Atlas portal (https://portal.gdc.cancer.gov/projects). Genome-wide alternative splicing events were obtained using SpliceSeq tool. Analyses were performed using GraphPad Prism 7 and R software. Key findings: Univariate Cox analysis identified 2406 AS events with prognostic significance. We built an interaction network based on these survival-related AS events. Unsupervised clustering analysis showed that patients in cluster 2 had a better prognosis than those in other clusters. The prognostic splicing factors and AS events were used to generate a splicing network. Seven prognostic signatures, developed based on the top three survival-related AS events, predicted the survival risk and may serve as independent indicators of unfavorable prognosis. Among these risk signatures, only the alternate promoter (AP) signature was upregulated in the mesenchymal subtype, which is characterized by a complex immune microenvironment. A high AP risk score indicated an overloaded local immune response and enriched immune cell infiltration, which may accelerate the progression of GBM.Significance: AS-related signatures may serve as predictors of prognosis as well as provide treatment targets and guidance for GBM patients.

show abstract

“…ITSN1-S promotes glioma development whereas ITSN1-L inhibits glioma progression both in vivo and in vitro. This opposing function of ITSN1-S and ITSN1-L is highly regulated by alternative splicing (44). Similarly, alternative splicing of CD99 leads to two isoforms, full-length (CD99wt) and a truncated short form (CD99sh) (45, 46).…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing

Nair

Narendradev

Nambiar

et al. 2019

Preprint

View full text Add to dashboard Cite

Lysosomal exocytosis and resealing of damaged plasma membrane play critical roles in physiological and pathological processes, including, restoration of cellular homeostasis and tumor invasion. However, to-date, only a few regulatory molecules of these biological processes have been identified. Moreover, no mutations in any of the known regulators of lysosomal exocytosis in primary tumors of patients have been characterized. Here we demonstrate that RNF167, a lysosomal associated ubiquitin ligase, negatively regulates lysosomal exocytosis by inducing perinuclear clustering of lysosomes. Importantly, we also characterized a set of novel natural mutations in RNF167, which are commonly found in diverse tumor types. We found that RNF167-K97N mutant, unlike the wild-type, localizes in the cytoplasm and does not promote perinuclear lysosomal clustering and that cells expressing RNF167-K97N exhibit dispersed lysosomes, increased exocytosis, and enhanced plasma membrane repair. Interestingly, these functional features of RNF167-K97N were shared with a naturally occurring short version of RNF167, i.e. isoform b. In brief, the results presented here reveal a novel role of RNF167 as well as its natural variants, RNF167-K97N and RNF167-b as an upstream regulator of lysosomal exocytosis and plasma membrane resealing which might play an important role in organelle dynamics or tumor progression or both.

show abstract

Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression

Cited by 25 publications

References 43 publications

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

Genome-Wide Profiling and Clinical Significance of Alternative Splicing Events in Glioblastoma

Naturally Occurring Shorter and Tumor-associated Mutant RNF167 Variants Facilitates Lysosomal Exocytosis and Plasma Membrane Resealing

Contact Info

Product

Resources

About