Alternative RNA splicing: contribution to pain and potential therapeutic strategy

Donaldson, Lucy F.; Beazley‐Long, Nicholas

doi:10.1016/j.drudis.2016.06.017

Cited by 37 publications

(29 citation statements)

References 122 publications

(160 reference statements)

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“…A majority of genes within the human genome are alternatively spliced to generate multiple transcripts, often encoding proteins with different or opposite function 1 , 2 . Under the circumstance of normal conditions, alternative splicing (AS) is precisely regulated to produce diverse protein isoforms for the demands of complex biological process 3 , 4 . If disordered, however, tumour cells generate aberrant proteins with inserted, missing, or altered functional domains which lead to tumorigenesis 5 .…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

Liu¹,

Li²,

Shen³

et al. 2018

J. Cancer

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Background: Emerging evidence suggested that aberrant alternative splicing (AS) is pervasive event in development and progression of cancer. However, the information of aberrant splicing events involved in colorectal carcinogenesis and progression is still elusive.Materials and Methods: In this study, splicing data of 499 colon adenocarcinoma cases (COAD) and 176 rectum adenocarcinoma (READ) with clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) to explore the changes of alternative splicing events in relation to the carcinogenesis and prognosis of colorectal cancer (CRC). Gene interaction network construction, functional and pathway enrichment analysis were performed by multiple bioinformatics tools.Results: Overall, most AS patterns were more active in CRC tissues than adjacent normal ones. We detected altogether 35391 AS events of 9084 genes in COAD and 34900 AS events of 9032 genes in READ, some of which were differentially spliced between cancer tissues and normal tissues including genes of SULT1A2, CALD1, DTNA, COL12A1 and TTLL12. Differentially spliced genes were enriched in biological process including muscle organ development, cytoskeleton organization, actin cytoskeleton organization, biological adhesion, and cell adhesion. The integrated predictor model of COAD showed an AUC of 0.805 (sensitivity: 0.734; specificity: 0.756) while READ predictor had an AUC of 0.738 (sensitivity: 0.614; specificity: 0.900). In addition, a number of prognosis-associated AS events were discovered, including genes of PSMD2, NOL8, ALDH4A1, SLC10A7 and PPAT.Conclusion: We draw comprehensive profiles of alternative splicing events in the carcinogenesis and prognosis of CRC. The interaction network and functional connections were constructed to elucidate the underlying mechanisms of alternative splicing in CRC.

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Section: Introductionmentioning

confidence: 99%

Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

Liu¹,

Li²,

Shen³

et al. 2018

J. Cancer

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“…During neuropathic pain development SRPK1 drives expression of pro-nociceptive VEGF-A xxx a at the level of the spinal cord. Therefore the development of SRPK1 targeted therapy, or other controls for alternative splicing, would be interesting targets for novel analgesic agent development (Donaldson and Beazley-Long, 2016). These findings highlight the importance of understanding control of RNA function, including alternative splicing in relation to pain, and considering specific interactions of splice factors in excitatory networks following peripheral nerve trauma.…”

Section: Resultsmentioning

confidence: 99%

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

Hulse

Drake

Bates

et al. 2016

Neurobiology of Disease

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Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord.Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons. Serine arginine protein kinase 1 (SRPK1) is the principal route of SRSF1 activation. Spinal SRPK1 inhibition attenuated SRSF1 activity, abolished neuropathic pain behaviors and suppressed central sensitization. SRSF1 was principally expressed in large diameter myelinated (NF200-rich) dorsal root ganglia sensory neurons and their excitatory central terminals (vGLUT1 + ve) within the dorsal horn of the lumbar spinal cord.Expression of pro-nociceptive VEGF-Axxxa within the spinal cord was increased after nerve injury, and this was prevented by SRPK1 inhibition. Additionally, expression of anti-nociceptive VEGF-Axxxb isoforms was elevated, and this was associated with reduced neuropathic pain behaviors. Inhibition of VEGF receptor-2 signaling in the spinal cord attenuated behavioral nociceptive responses to mechanical, heat and formalin stimuli, indicating that spinal VEGF receptor-2 activation has potent pro-nociceptive actions. Furthermore, intrathecal VEGF-A165a resulted in mechanical and heat hyperalgesia, whereas the sister inhibitory isoform VEGF-A165b resulted in anti-nociception. These results support a role for myelinated fiber pathways, and alternative pre-mRNA splicing of factors such as VEGF-A in the spinal processing of neuropathic pain. They also indicate that targeting pre-mRNA splicing at the spinal level could lead to a novel target for analgesic development.

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“…Genome-wide approaches suggest that a remarkable amount remains to be uncovered about mechanisms of non-coding RNA, local translation, RNA-decay, and their relationship to pain. For example, noxious stimuli alter patterns of alternative splicing as well as changes in 3′ end utilization ( Donaldson and Beazley-Long, 2016 , Hirai et al, 2017 ). The use of a distal 3′ end isoform of Nav 1.8 mRNA imparts axonal localization after chronic injury.…”

Section: Rna-binding Proteins That Are Involved In Painmentioning

confidence: 99%

RNA-binding proteins as targets for pain therapeutics

Peña

Campbell

2018

Neurobiology of Pain

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RNA-protein interactions permeate biology. Transcription, translation, processing, and mRNA decay all hinge on widespread use of regulatory information decoded by RNA-binding proteins. The final committed step of protein synthesis, translation, is intimately linked to nociceptor excitability. Understanding the factors that control translation is essential as nociceptor plasticity is a hallmark of persistent pain. Here, we review the growing body of evidence for widespread involvement of RNA-binding proteins in pain. Many of the relevant factors have been implicated in post-transcriptional and translational mechanisms of mRNA control. We propose that recent advances in the development of RNA-based therapeutics provide a potential means to exploit our current understanding of liaisons between RNAs and proteins for therapeutic purposes.

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Alternative RNA splicing: contribution to pain and potential therapeutic strategy

Cited by 37 publications

References 122 publications

Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

Alternative splicing events implicated in carcinogenesis and prognosis of colorectal cancer

The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain

RNA-binding proteins as targets for pain therapeutics

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