Insights into the connection between cancer and alternative splicing

Kim, Eddo; Goren, Amir; Ast, Gil

doi:10.1016/j.tig.2007.10.001

Cited by 149 publications

(128 citation statements)

References 23 publications

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“…Many oncogenes and tumor suppressors are differentially spliced in cancer cells, and it has been shown that many of these cancer-specific isoforms contribute to the transformed phenotype of cancer cells (Venables 2004;Srebrow and Kornblihtt 2006;Kim et al 2008). 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).…”

Section: Introductionmentioning

confidence: 95%

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

RNA

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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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Section: Introductionmentioning

confidence: 95%

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

RNA

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“…Unregulated alternative splicing is likely to be detected in diseased cells, which is relevant to clinical diagnostics (23,24). Indeed, at least 15% of all disease causing single base-pair mutations affect splicing and cause phenotypic differences (25,26).…”

Section: Altered Rna-rbp Network In Diseasementioning

confidence: 99%

Emerging roles of RNA and RNA-binding protein network in cancer cells

Kim

Hur²,

Jeong³

2009

BMB Reports

139

123

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“…4 Splicing, the removal of introns and joining of exons from nascent pre-mRNA, has gained attention as a target for cancer therapy given the distinct splicing patterns identified both in tumor cells and metastatic tumor populations. 5,6 Recently, a series of studies identified heterozygous missense mutations in U2AF1 and splicing factor 3B subunit 1 (SF3B1) genes associated with myelodysplastic syndromes, and have shown that SF3B1 is frequently mutated in myelodysplastic syndromes, 7,8 and CLL. 9,10 This, combined with the identification of small molecules that target the spliceosome, motivated us to explore the application of these agents to CLL.…”

Section: Introductionmentioning

confidence: 99%