Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma

Cheung, Hannah; Corley, Lynda; Fuller, Gregory N.; McCutcheon, Ian E.; Cote, Gilbert J.

doi:10.1038/modpathol.3800635

Cited by 47 publications

(44 citation statements)

References 37 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To further address the mechanisms of splicing of the neuron-specific, EGFR-regulatory ANXA7 exon in these tumors, we identified 3 putative splicing factors among genes differentially expressed in glioblastomas (56): 2 promoters of exon inclusion downregulated in glioblastoma, RNA-binding protein, fox-1 homolog (C. elegans) 1 (RBFOX1) (57) and CUGBP, Elav-like family member 2 (CUGBP2) (58); and 1 promoter of exon exclusion upregulated in glioblastoma, the hnRNP PTBP1 (46,47). We first confirmed the differential expression of these splicing factors in glioblastomas and glioblastoma-derived cell cultures ( Figure 2A and Supplemental Figure 2, A-C), demonstrating low expression of RBFOX1 and CUGBP2 and high expression of PTBP1 in glioblastoma tumor and glioblastoma cultures compared with levels observed in normal brain.…”

Section: Figurementioning

confidence: 99%

“…Here, we define a role for lineage-specific splicing of a brain-enriched cassette exon in ANXA7 in the transforming deregulation of the EGFR oncoprotein during brain tumor progression. We show that the splicing is mediated by the heterogeneous nuclear ribonucleoprotein (hnRNP) polypyrimidine tract-binding protein 1 (PTBP1), an RNA-binding protein that is repressed during normal neurogenesis to allow the differentiation of progenitor cells into mature neurons (44,45), but that is highly expressed in brain tumors (46,47). Our observations illustrate the potential for contextspecific splicing of a tissue-regulated alternative exon in a human tumor suppressor to eliminate its function and, by deregulating oncogenic signaling, contribute to tumor progression in the tissue of origin.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

View full text Add to dashboard Cite

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.

show abstract

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Some of these changes can arise from mutations at either the splice sites or within proximal splicing enhancer or silencer elements or from perturbations of transacting splicing factors (8). Examples of trans-acting factors that affect alternative splicing in cancer include ASF/SF2, PTB, and SRPK1 (17)(18)(19)(20). Indeed, staining with PTB antibody was higher in invasive ovarian tumors than low malignant potential tumors and even lower in benign tumors (19).…”

Section: Introductionmentioning

confidence: 99%

Multiple Alternative Splicing Markers for Ovarian Cancer

et al. 2008

View full text Add to dashboard Cite

Intense efforts are currently being directed toward profiling gene expression in the hope of developing better cancer markers and identifying potential drug targets. Here, we present a sensitive new approach for the identification of cancer signatures based on direct high-throughput reverse transcription-PCR validation of alternative splicing events. This layered and integrated system for splicing annotation (LISA) fills a gap between high-throughput microarray studies and high-sensitivity individual gene investigations, and was created to monitor the splicing of 600 cancer-associated genes in 25 normal and 21 serous ovarian cancer tissues. Out of >4,700 alternative splicing events screened, the LISA identified 48 events that were significantly associated with serous ovarian tumor tissues. In a further screen directed at 39 ovarian tissues containing cancer pathologies of various origins, our ovarian cancer splicing signature successfully distinguished all normal tissues from cancer. High-volume identification of cancer-associated splice forms by the LISA paves the way for the use of alternative splicing profiling to diagnose subtypes of cancer.

show abstract

“…Increases in the splicing factor polypyrimidine tract-binding protein (PTBP1, also known as hnRNPI) that are associated with glioma malignancy could have similar oncogenic effects (6). PTBP1 has been reported to play a key role in pre-mRNA splicing in cancer.…”

Section: Introductionmentioning

confidence: 99%

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

Takahashi

Nishimura

Kagawa

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Polypyrimidine tract-binding protein (PTBP1) is an RNAbinding protein with various molecular functions related to RNA metabolism and a major repressive regulator of alternative splicing, causing exon skipping in numerous alternatively spliced pre-mRNAs. Here, we have investigated the role of PTBP1 in colorectal cancer. PTBP1 expression levels were significantly overexpressed in cancerous tissues compared with corresponding normal mucosal tissues. We also observed that PTBP1 expression levels, c-MYC expression levels, and PKM2: PKM1 ratio were positively correlated in colorectal cancer specimens. Moreover, PTBP1 expression levels were positively correlated to poor prognosis and lymph node metastasis. In analyses of colorectal cancer cells using siRNA for PTBP1, we observed that PTBP1 affects cell invasion, which was partially correlated to CD44 splicing, and this correlation was also confirmed in clinical samples. PTBP1 expression also affected anchorage-independent growth in colorectal cancer cell lines. PTBP1 expression also affected cell proliferation. Using timelapse imaging analysis, PTBP1 was implicated in prolonged G 2 -M phase in HCT116 cells. As for the mechanism of prolonged G 2 -M phase in HCT116 siPTBP1 cells, Western blotting revealed that PTBP1 expression level was correlated to CDK11 p58 expression level, which was reported to play an important role on progression to complete mitosis. These findings indicated that PTBP1 is a potential therapeutic target for colorectal cancer.

show abstract

Polypyrimidine tract binding protein and Notch1 are independently re-expressed in glioma

Cited by 47 publications

References 37 publications

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

Multiple Alternative Splicing Markers for Ovarian Cancer

Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

Contact Info

Product

Resources

About