Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

Matteo, Anna Di; Belloni, Elisa; Pradella, Davide; Cappelletto, Ambra; Volf, N. V.; Zacchigna, Serena; Ghigna, Claudia

doi:10.1186/s13046-020-01753-1

Cited by 21 publications

(22 citation statements)

References 209 publications

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“…For the majority of protein isoforms generated through AS in ECs, functional role remains obscure 35 . AS is particularly frequent in cell-surface molecules and receptors, thus potentially affecting interactome networks as well as downstream signaling pathways 36 .…”

Section: Resultsmentioning

confidence: 99%

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

et al. 2021

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The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.

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Section: Resultsmentioning

confidence: 99%

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

et al. 2021

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“…Aberrant AS is demonstrated as a key mechanism that generates multiple RNA variants to regulate protein diversity and enlarge the complexity regulation in many diseases, including cancers 42 , 43 . SRSF1 protein has been reported to regulate apoptotic control in human cancer cells through alternative splicing pathway 44 , 45 .…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1

et al. 2021

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Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.

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“…Aberrant splicing is commonly observed in cancer [ 9 , 10 , 11 ]. Indeed, cancer-associated alterations generate splice variants involved in all of the different hallmarks of cancer, including cancer cell survival, proliferation, metastasis, angiogenesis, and chemoresistance [ 12 , 13 , 14 ]. Aberrant splicing can arise from alterations in the components of the splicing cycle, such as mutations in splicing sites and/or spliceosome components, or from mutations or altered expression of non-spliceosome RNA binding proteins, which assist splice site selection and accurate splicing.…”

Section: Introductionmentioning

confidence: 99%

Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

Niño

Perrotolo

Polo

2022

Cancers

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Splicing alterations have been widely documented in tumors where the proliferation and dissemination of cancer cells is supported by the expression of aberrant isoform variants. Splicing is catalyzed by the spliceosome, a ribonucleoprotein complex that orchestrates the complex process of intron removal and exon ligation. In recent years, recurrent hotspot mutations in the spliceosome components U1 snRNA, SF3B1, and U2AF1 have been identified across different tumor types. Such mutations in principle are highly detrimental for cells as all three spliceosome components are crucial for accurate splice site selection: the U1 snRNA is essential for 3′ splice site recognition, and SF3B1 and U2AF1 are important for 5′ splice site selection. Nonetheless, they appear to be selected to promote specific types of cancers. Here, we review the current molecular understanding of these mutations in cancer, focusing on how they influence splice site selection and impact on cancer development.

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Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

Cited by 21 publications

References 209 publications

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1

Recurrent Spliceosome Mutations in Cancer: Mechanisms and Consequences of Aberrant Splice Site Selection

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