The Evolutionarily Conserved Cassette Exon 7b Drives ERG's Oncogenic Properties

Jumbe, Samantha L.; Porazinski, Sean; Oltean, Sebastian; Mansell, Jason P.; Vahabi, Bahareh; Wilson, Ian; Ladomery, Michael

doi:10.1016/j.tranon.2018.09.001

Cited by 6 publications

(11 citation statements)

References 31 publications

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“…Mutation of the ERK docking site to AAAP prevents phosphorylation of ERG by ERK 15 . In our hands, and consistent with these findings, the reduction of exon 7b inclusion induced with splice-switching oligonucleotides (SSOs) resulted in decreased cell proliferation, migration and increased apoptosis 14 confirming that exon 7b contributes to ERG's oncogenic potential. These findings are consistent with earlier observations by Wang and colleagues who demonstrated that ERG isoforms that include 7b are more efficient in driving cell proliferation 16 .…”

Section: Introductionsupporting

confidence: 84%

“…SSOs can promote the inclusion of desirable exons (e.g. TOES, targeted oligonucleotide enhancers of splicing 29 ), or induce exon skipping as illustrated by our own ERG exon 7b SSO 14 and Eteplirsen 27 . Another success story is Nusinersen, an FDA-approved ASO (Spinraza, Biogen) that is used to treat spinal muscular atrophy (SMA).…”

Section: Introductionmentioning

confidence: 99%

“…The 24 amino-acids encoded by the evolutionarily-conserved exon 7b include an extracellular-signal-regulated kinase (ERK) docking site (with consensus sequence FxFP) 14 .…”

Section: Introductionmentioning

confidence: 99%

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Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

Hobson

Perry

et al. 2020

Br J Cancer

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BACKGROUND: The ERG oncogene is activated in 50% of prostate cancers. We have designed morpholino-based oligonucleotides that target the ERG oncogene by inducing skipping of exon 4. METHODS: We designed antisense splice-switching morpholino oligonucleotides (SSOs) that target exon 4. We tested their efficacy in ERG-positive VCaP prostate cancer and MG63 osteosarcoma cell lines. We measured their effect on ERG expression, cell proliferation, migration and apoptosis in cell lines, xenografts and a radical prostatectomy sample. RESULTS: SSOs induced exon 4 skipping, reducing ERG levels up to 96 hours following transfection. SSO-induced ERG reduction decreased cell proliferation, cell migration and increased apoptosis. We observed a reduction in cyclin D1, c-Myc, β-catenin and a marker of activated Wnt signalling, p-LRP6. SSOs reduced the growth of MG63 xenografts in mice. We also demonstrated that the SSOs cause a reduction in ERG expression in a patient-derived radical prostatectomy sample ex vivo. CONCLUSIONS: We have successfully tested morpholino-based SSOs that cause a marked reduction in ERG expression, resulting in decreased cell proliferation, a reduced migratory phenotype and increased apoptosis. Our initial tests on mouse xenografts and a human prostate cancer radical prostatectomy specimen indicate that SSOs can be effective for ERG oncogene targeting in vivo.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

Hobson

Perry

et al. 2020

Br J Cancer

Self Cite

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“…Shon et al [39] indicated that ERG is highly expressed in osteosarcoma tissues, and suggested ERG as a possible marker of chondroid/ cartilaginous differentiation. In the study conducted by Jumbe et al [40], ERG was demonstrated to increase the bone matrix formation and promote osteosarcoma development via activating the transcription of TNSALP . Consistent with their studies, we also observed the upregulation of ERG in osteosarcoma cells and the pro-proliferating and pro-metastatic effect of ERG.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p

Zhao

Qin

Zhang

et al. 2019

Aging

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Exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) promote osteosarcoma cell proliferation and migration, while the underlying mechanism remains unknown. Since the long non-coding RNA PVT1 has been reported to be upregulated in osteosarcoma cells and contributes to its growth and metastasis, we aim to investigate whether BMSC-derived exosomes promote osteosarcoma growth and metastasis via transporting PVT1 into osteosarcoma cells. The PVT1 expression in BMSC-derived exosomes was markedly higher than that in osteosarcoma cell-derived exosomes. The co-culturing of BMSC-derived exosomes and osteosarcoma cells (Saos-2, MG-63, and MNNG/HOS cell lines) significantly raised PVT1 expression of osteosarcoma cells. The direct binding between PVT1 and the oncogenic protein ERG was confirmed using RNA immunoprecipitation and RNA pull-down assays, and the transported PVT1 promotes osteosarcoma cell proliferation and migration via inhibiting degradation and ubiquitination of ERG. PVT1 also increased ERG expression through sponging miR-183-5p. In summary, our findings indicated that BMSC-derived exosomes encapsulate PVTl and transport it into osteosarcoma cells, and the transported PVT1 promotes tumor growth and metastasis by inhibiting ubiquitination and promoting expression of ERG in osteosarcoma cells. These data provide a novel insight into the mechanism of BMSC-derived exosomes in affecting osteosarcoma progression.

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“…ERG is a widely investigated oncogene, involving in hematopoiesis, chondrocyte maturation, and bone development and in apoptosis and cell migration. [18] Due to the gene fusion with the promoter region of the androgen-induced TMPRRSS2 gene, ERG has become highly correlated with prostate cancer development. [19] RRM2, as the small subunit of ribonucleotide reductase, is an essential enzyme involved in DNA replication and repair.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of competing endogenous RNA network and 3-mRNA signature predicting survival in papillary renal cell cancer

Zhu¹,

Tan²,

Liang³

et al. 2019

Medicine

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Long non-coding RNAs (lncRNAs) can act as competing endogenous RNAs (ceRNAs) to exert significant roles in regulating the expression of mRNAs by sequestering and binding miRNAs. To elucidate the functional roles and regulatory mechanism of lncRNAs in papillary renal cell cancer (pRCC), we conducted a comprehensive analysis of ceRNA network and constructed a mRNA signature to predict prognosis of pRCC. We collected mRNAs and lncRNAs expression profiles of 289 pRCC samples and 32 normal renal tissues, and miRNA expression profiles of 292 pRCC samples and 34 normal samples from The Cancer Genome Atlas (TCGA) database. Differential expressions of RNAs were evaluated by the “edgeR” package in R. Functional enrichment analysis of DEmRNA was performed by DAVID 6.8 and KEGG, while PPI network of top 200 DEmRNAs was conducted using the STRING database. The univariate and multivariate Cox regression were conducted to figure out the candidate DEmRNAs with predictive values in prognosis. Receiver operator characteristic (ROC) curve estimation was performed to achieve the area under the curve (AUC) of the ROC curve to judge mRNA-associated prognosic model. A ceRNA network was established relying on the basis of combination of lncRNA-miRNA interactions and miRNA-mRNA interactions. A total of 1928 DEmRNAs, 981 DElncRNAs, and 52 DEmiRNAs were identified at significance level of |log 2 Fold Change |>2 and adjusted P -value < .01. A 3-mRNA signatures consisting of ERG, RRM2, and EGF was constructed to predict survival in pRCC. Moreover, a pRCC-associated ceRNA network was constructed, with 57 lncRNAs, 11 miRNAs, and 28 mRNAs. Our study illustrated the regulatory mechanism of ceRNA network in papillary renal cancer. The identified mRNA signatures could be used to predict survival of pRCC.

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The Evolutionarily Conserved Cassette Exon 7b Drives ERG's Oncogenic Properties

Cited by 6 publications

References 31 publications

Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

Targeting the ERG oncogene with splice-switching oligonucleotides as a novel therapeutic strategy in prostate cancer

Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p

Comprehensive analysis of competing endogenous RNA network and 3-mRNA signature predicting survival in papillary renal cell cancer

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