Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer

He, Xijing; Arslan, Ahmet Dirim; Pool, Mark; Ho, Tsui-Ting; Darcy, Kathleen M.; Coon, John S.; Beck, William T.

doi:10.1038/onc.2010.426

Cited by 92 publications

(90 citation statements)

References 47 publications

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“…Upregulation and functional association with various types of cancer have been reported for SRSF3 (66)(67)(68)72) and hnRNP A1 (73-76), which we have identified here as two crucial trans-acting factors for alternative splicing of HPV18 pre-mRNAs. Thus, our observations indicate that the manipulation of alternative splicing regulation may be a potential therapeutic target for HPV-related cancer.…”

Section: Discussionsupporting

confidence: 59%

“…In addition to its regulation of viral gene expression, SRSF3 has been characterized as an oncogenic factor (66)(67)(68), and it effects global change of the gene expression of hundreds of mammalian genes to maintain cell homeostasis (34,39,(69)(70)(71). Upregulation and functional association with various types of cancer have been reported for SRSF3 (66)(67)(68)72) and hnRNP A1 (73-76), which we have identified here as two crucial trans-acting factors for alternative splicing of HPV18 pre-mRNAs.…”

Section: Discussionmentioning

confidence: 64%

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Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCEExpression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.H igh-risk human papillomavirus (HPV) is associated with more than 95% of cervical cancer, 40 to 90% of anogenital cancer, and 10 to 60% of oropharyngeal cancer with geographic variation (1). Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regu...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 64%

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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“…SRSF3 is an essential gene: Srsf3 knockout (KO) in mice results in an early lethal phenotype, suggesting a fundamental and nonredundant function for each SR protein in embryonic development (Jumaa et al 1999). In human tumors, SRSF3 is overexpressed in ovarian, cervical, lung, colon, breast, stomach, skin, bladder, thyroid, liver, and kidney cancer (He et al 2004(He et al , 2011Jia et al 2010;Iborra et al 2013), at least in part due to copy-number changes in Chr. 6p21.…”

Section: Srsf3-serine/arginine-rich Splicing Factormentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

227

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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“…Reduction of SRSF3 led to the cell cycle arrest at G1 by downregulating expression of the G1 -to-S checkpoint-related genes (23). A subset of SRSF proteins are overexpressed in several types of tumors, as evidenced by amplification of SRSF1 mainly in breast cancers activated by the pro-oncogenic transcription factor Myc (4,12), and enhanced expression of SRSF3 in ovarian and colon cancers (8,19). However, the distinct contribution of SRSF7 to cell growth or tumor progression has not been fully understood.…”

Section: Introductionmentioning

confidence: 99%

Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells

et al. 2016

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: Serine/arginine-rich splicing factors (SRSFs) play wide-ranging roles in gene expression through post-transcriptional regulation as well as pre-mRNA splicing. SRSF7 was highly expressed in colon cancer tissues, and its knockdown inhibited cell growth in colon cancer cells (HCT116) in association with altered expression of 4,499 genes. The Ingenuity Pathway Analysis revealed that cell cycle-related canonical pathways were ranked as the highly enriched category in the affected genes. Western blotting confirmed that p21, a master regulator in cell cycle, was increased without any induction of p53 in SRSF7 knockdown cells. Furthermore, cyclin-dependent kinase 2 and retinoblastoma protein were remained in the hypophosphorylated state. In addition, the SRSF7 knockdown -induced cell growth inhibition was observed in p53-null HCT116 cells, suggesting that p53-independent pathways were involved in the SRSF7 knockdown-induced cell growth inhibition. The reduction of SRSF7 stabilized cyclin-dependent kinase inhibitor 1A (CDKN1A) mRNA without any activation of the CDKN1A promoter. Interestingly, SRSF7 knockdown also blocked p21 degradation. These results suggest that the reduction of SRSF7 post-transcriptionally regulates p21 induction at the multistep processes. Thus, the present findings disclose a novel, important role of SRSF7 in cell proliferation through regulating p21 levels.

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Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer

Cited by 92 publications

References 47 publications

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Splicing-factor alterations in cancers

Serine/arginine-rich splicing factor 7 regulates p21-dependent growth arrest in colon cancer cells

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