The splicing factor <scp>SRSF6</scp> is amplified and is an oncoprotein in lung and colon cancers

Cohen-Eliav, Michal; Golan-Gerstl, Regina; Siegfried, Zahava; Andersen, Claus Lindbjerg; Thorsen, Kasper; Ørntoft, Torben F.; Mu, David; Karni, Rotem

doi:10.1002/path.4129

Cited by 130 publications

(128 citation statements)

References 54 publications

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“…The SRSF6 gene encodes a protein that is involved in mRNA splicing and its overexpression is suggested to contribute to the development of lung and colon cancers. 20 C. pneumoniae seropositivity may be a risk factor for lung cancer, with higher anti-C. pneumoniae antibody titer correlated with cancer risk. 21 Although the mechanism by which infection with C. pneumoniae may increase the risk of lung cancer is not known, one possible explanation is that it may induce irregular apoptosis in tissues.…”

Section: Discussionmentioning

confidence: 98%

Genome-wide genetic investigation of serological measures of common infections

et al. 2015

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Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from 41300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using 1 million SNPs. Significant linkage (lod scores 43.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P = 5.3 × 10 −8 ). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels.

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Section: Discussionmentioning

confidence: 98%

Genome-wide genetic investigation of serological measures of common infections

et al. 2015

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“…For example, alterations in alterative splicing of the APC, K-Ras and TP53 genes have been implicated in the context of multiple carcinogenesis of CRC 15 . In addition, upregulation of typical SR proteins such as SRSF1 and SRSF6 was previously observed in colon cancers, although misregulated splicing events by them have not been identified 33,34 . These findings suggested that genetic lesions or dysregulation of splicing factors that affect alternative splicing are likely to contribute significantly to the aetiology of disease.…”

Section: Discussionmentioning

confidence: 99%

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

et al. 2014

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Bcl-2-associated transcription factor 1 (BCLAF1) is known to be involved in multiple biological processes. Although several splice variants of BCLAF1 have been identified, little is known about how BCLAF1 splicing is regulated or the contribution of alternative splicing to its developmental functions. Here we find that inclusion of alternative exon5a was significantly increased in colorectal cancer (CRC) samples. Knockdown of the BCLAF1 protein isoform resulting from exon5a inclusion inhibited growth and that its overexpression increased tumorigenic potential. We also found that the splicing factor SRSF10 stimulates inclusion of exon5a and has growth-inducing activity. Importantly, the upregulation of SRSF10 expression observed in clinical CRC samples parallels the increased inclusion of BCLAF1 exon5a, both of which are associated with higher tumour grade. These findings identify SRSF10 as a key regulator of BCLAF1 pre-mRNA splicing and the maintenance of oncogenic features in human colon cancer cells.

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“…A growing body of evidence suggests that alternative splicing factors play a major role in cancer development and progression (Karni et al 2007;Golan-Gerstl et al 2011;Quesada et al 2012;Cohen-Eliav et al 2013). Moreover, genomewide deep sequencing studies conducted recently on several types of cancer or premalignant diseases discovered mutations in splicing factors and suggest that these mutations are driver mutations (Papaemmanuil et al 2011;Imielinski et al 2012;Quesada et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, mutations in several components of the spliceosome were recently discovered in several cancers and are predicted to be driver mutations, providing further confirmation that splicing factors are indeed important players in cancer development (Papaemmanuil et al 2011;Quesada et al 2012). However, there is only limited information regarding the causal/functional role of alternative splicing regulators in cancer development and progression (Karni et al 2007;Jia et al 2010;Golan-Gerstl et al 2011;Lefave et al 2011;Anczukow et al 2012;Cohen-Eliav et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development

Shilo¹,

Hur²,

Denichenko³

et al. 2014

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In recent years, it has become clear that splicing factors play a direct role in cancer development. We showed previously that splicing factors SRSF1, SRSF6, and hnRNP A2/B1 are up-regulated in several cancers and can act as oncogenes when up-regulated. Here we examined the role of splicing factors hnRNP A1/A1b and hnRNP A2/B1 in hepatocellular carcinoma (HCC). We show that the splicing factors hnRNP A1 and hnRNP A2 are up-regulated in HCC tumors derived from inflammation-induced liver cancer mouse model. Overexpression of hnRNP A1 or hnRNP A2, but not the splicing isoform hnRNP B1, induced tumor formation of immortalized liver progenitor cells, while knockdown of these proteins inhibited anchorage-independent growth and tumor growth of human liver cancer cell lines. In addition, we found that cells overexpressing hnRNP A2 showed constitutive activation of the Ras-MAPK-ERK pathway. In contrast, knockdown of hnRNP A2 inhibited the Ras-MAPK-ERK pathway and prevented ERK1/2 activation by EGF. Moreover, we found that hnRNP A2 regulates the splicing of A-Raf, reducing the production of a short dominant-negative isoform of A-Raf and elevating the full-length A-Raf transcript. Taken together, our data suggest that hnRNP A2 up-regulation in HCC induces an alternative splicing switch that down-regulates a dominant-negative isoform of A-Raf, leading to activation of the Raf-MEK-ERK pathway and cellular transformation.

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The splicing factor SRSF6 is amplified and is an oncoprotein in lung and colon cancers

Cited by 130 publications

References 54 publications

Genome-wide genetic investigation of serological measures of common infections

Genome-wide genetic investigation of serological measures of common infections

BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development

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