RON alternative splicing regulation in primary ovarian cancer

Mayer, Sebastian; Hirschfeld, Marc; Jaeger, Markus; Pies, Susanne; Iborra, Séverine; Erbes, Thalia; Stickeler, Elmar

doi:10.3892/or.2015.3995

Cited by 19 publications

(25 citation statements)

References 34 publications

(31 reference statements)

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“…A strong effect is observed on splicing of the tyrosine kinase receptor RON, linking these proteins to cancer progression. More than 20 different cancers might be caused by expression of altered RON isoforms, including glioblastoma, pancreatic, breast, ovarian, and colon cancers (Braun et al, ; Chakedis et al, ; Lefave et al, ; Mayer et al, ; Z. Wang et al, ). The alternative isoform RONdelta165, derived from exon 11 skipping, leads to constitutive phosphorylation increasing EMT, therefore increasing cell migration and invasiveness, leading to a tumoral phenotype in different cells.…”

Section: Invasionmentioning

confidence: 99%

Splicing and cancer: Challenges and opportunities

2019

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Constitutive splicing is favored in strong splice sites, which have the conserved consensus sequences at 5 0 (CAG|GUAAGU) and 3 0 (NYAG|G) splice sites. Exons are usually shorter sequences, ranging from 50 to 250 bp, whereas introns can have broader length variation, from <100 bp to more than 1,000 bp, and around 20% of human introns are larger than 5 kb (Lander et al., 2001). In addition to constitutive exon splicing, the presence of alternative splice sites leads to variable ways to mature an mRNA ( Figure 2). Exons and introns might host alternative splice sites, which are similar to, but usually not as strong as, consensus splice sites (Fu & Ares, 2014;Kornblihtt et al., 2013). If a 5 0 or 3 0 alternative site lies within an exon, part of this exon might be read as an intron. Also, alternative splicing can lead to exon skipping, in which a constitutive 3 0 splice site fails to be recognized and assembly of spliceosome proceeds to the next available 3 0 splice site, which can result in exclusion of an exon. Alternatively, 5 0 splice sites might not be read as well, resulting in intron retention. In some transcripts, a mutual exclusion of exons might take place generating different messages . Cryptic splice sites are similar to consensus sites, but they are usually recognized only after a mutation in the gene, or of a spliceosome component, leading to alterations in the final message. In breast cancer, mutations in splicing factor 3B subunit 1 (SF3B1), for example, induce the use of cryptic 3 0 splice sites (DeBoever et al., 2015). Single nucleotide variants (SNVs) of 1,812 tumor samples were analyzed by whole-exome sequencing and revealed exon skipping and intron retention were among the most frequently observed alternative splicing events (Jung et al., 2015; Box 1).Alternative splicing mechanisms are dependent on recognition of splice site sequences in the pre-mRNA, which in turn depends on both the strength of sequences as well as the presence of proteins and signals that guide the spliceosome to these regions. Alternative exons in humans and mice are surrounded by more conserved regulatory sequences than constitutive exons, indicating the former ones are under strict regulation. Consistently, 30-50% of ISEs are located nearby alternative exons (Yeo, Van Nostrand, & Liang, 2007). Interestingly, ISEs and ESSs show a positional overlap in different pre-mRNA substrates, indicating the regulation depends on their positioning with respect to the 5 0 upstream exon and the bound proteins (Y. Wang et al., 2012). The ISSs can interfere with exon inclusion in different pre-mRNAs, and regulate 5 0 splice site choice, therefore, exerting alternative splicing regulation (Y. Wang et al., 2013). In this sense, mutations in exonic and intronic sequences are critical and might affect the balance of regulatory sequences and also their activity, since most effects in splicing are location-dependent. Intronic mutations are commonly associated with nonsense-mediated decay responses, caused by an increased rate of premature stop ...

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Section: Invasionmentioning

confidence: 99%

Splicing and cancer: Challenges and opportunities

2019

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“…Additionally, the RONΔ165 variant is formed by an in-frame exon 11 and results in the accumulation of the single-chain pro-RONΔ165 [97]. Furthermore, RONΔ165 is constitutively phosphorylated by oligomerization due to the deletion of exon 11 and is involved in mobile and invasive phenotypes [97,98].…”

Section: Ronmentioning

confidence: 99%

“…RONΔ170 is a defective variant, the alternative splicing of which generates the loss of exon 19, which leads to the absence of kinase activity, inhibiting the oncogenic activity mediated by another oncogenic variant, RONΔ160 [97,98]. RONΔ160 results from an in-frame deletion of 109 amino acids encoded by exons 5 and 6 [95,97].…”

Section: Ronmentioning

confidence: 99%

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Influence of transcriptional variants on metastasis

Poloni

Bonatto

2018

RNA Biology

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Cancer metastasis is defined as the dissemination of malignant cells from the primary tumor site, leading to colonization of distant organs and the establishment of a secondary tumor. Metastasis is frequently associated with chemoresistance and is the major cause of cancer-related mortality. Metastatic cells need to acquire the ability to resist to stresses provided by different environments, such as reactive oxygen species, shear stress, hemodynamic forces, stromal composition, and immune responses, to colonize other tissues. Hence, only a small population of cells has a metastasis-initiating potential. Several studies have revealed the misregulation of transcriptional variants during cancer progression, and many splice events can be used to distinguish between normal and tumoral tissue. These variants, which are abnormally expressed in malignant cells, contribute to an adaptive response of tumor cells and the success of the metastatic cascade, promoting an anomalous cell cycle, cellular adhesion, resistance to death, cell survival, migration and invasion. Understanding the different aspects of splicing regulation and the influence of transcriptional variants that control metastatic cells is critical for the development of therapeutic strategies. In this review, we describe how transcriptional variants contribute to metastatic competence and discuss how targeting specific isoforms may be a promising therapeutic strategy.

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“…These processes were growth factor self-sufficiency; insensitivity to growth inhibitory signals; limitless replicative potential; the ability to evade apoptosis; the ability to sustain angiogenesis; the ability to invade tissues and metastasize; the ability to evade the immune system; the presence of inflammation; the tendency towards genomic instability; and deregulated metabolism. regulates many of these processes involved in tumorigenesis and development (9)(10)(11)(12)(13)(14)(15)(16)(17). Accordingly, deregulated alternative splicing is considered to be a key feature of cancer and an opportunity to identify cancer biomarkers (18).…”

Section: Introductionmentioning

confidence: 99%

Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines

Liang

et al. 2015

Oncology Reports

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Abstract. Alternative splicing is a near-ubiquitous phenomenon with important roles in human diseases, including cancers. Splice-switching oligonucleotides (SSOs) have emerged as a class of antisense therapeutics that modulate alternative splicing by hybridizing to the pre-mRNA splice site. The Bcl-x gene is alternatively spliced to express anti-apoptotic Bcl-xL and pro-apoptotic Bcl-xS. Bcl-xL expression is upregulated in many cancers and is considered a general mechanism by which cancer cells evade apoptosis. By redirecting Bcl-x pre-mRNA splicing from Bcl-xL to Bcl-xS, SSO exerted pro-apoptotic and chemosensitizing effects in various cancer cell lines. In this study, we investigated the effects of SSO targeting Bcl-x premRNA in human glioma cell lines. First, we performed reverse transcription-polymerase chain reaction (RT-PCR) and western blotting to determine the mRNA and protein expression levels of Bcl-xL in glioma cell lines (U87 and U251) and a normal human astrocyte cell line (HA1800). Then, the Bcl-x SSO was designed to bind to the downstream 5' alternative splice site of exon 2 in Bcl-x pre-mRNA and was modified using 2'-O-methoxyethyl-phosphorothioate. An oligonucleotide targeting aberrantly spliced human β-globin intron was used as a negative control. The SSOs were delivered with a cationic lipid into glioma and astrocyte cell lines. The antitumor effects of the SSOs were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and flow cytometry, and the switch in production from Bcl-xL to Bcl-xS was analyzed by RT-PCR and western blotting. Bcl-xL mRNA and protein were highly expressed in both glioma cell lines. The Bcl-x SSO modified Bcl-x pre-mRNA splicing and had pro-apoptotic effects on the glioma cell lines. By contrast, the lipid alone and the control SSO did not affect Bcl-xL expression or induce apoptosis. Our study demonstrated the antitumor activity of an SSO that targets Bcl-x pre-mRNA splicing in glioma cell lines. Bcl-x SSO may be a potential strategy for treating gliomas. IntroductionAlternative splicing is the process by which splice sites in precursor messenger RNA (pre-mRNA) are differentially selected and paired to produce multiple mature mRNAs and protein isoforms with distinct structural and functional properties. Alternative splicing is a very accurate, efficient, and extraordinarily flexible process that regulates many major aspects of eukaryotic cell biology. Approximately 95% of human genes with multiple exons undergo alternative splicing during pre-mRNA maturation (1-3). In addition to its role in human proteome diversity, alternative splicing is now accepted to play important roles in human diseases, including diabetes, neurodegenerative diseases, and cancer (4-6).Aberrant alternative splicing has two major roles in cancer by promoting the emergence of a cancer-specific isoform or disturbing the balanced expression of normally expressed isoforms in cancer cells (7). During tumor growth and development, and during oncogenesis, cells progress through ...

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RON alternative splicing regulation in primary ovarian cancer

Cited by 19 publications

References 34 publications

Splicing and cancer: Challenges and opportunities

Splicing and cancer: Challenges and opportunities

Influence of transcriptional variants on metastasis

Pro-apoptotic effects of splice-switching oligonucleotides targeting Bcl-x pre-mRNA in human glioma cell lines

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