Pre-mRNA splicing in cancer: the relevance in oncogenesis, treatment and drug resistance

Wojtuszkiewicz, Anna; Assaraf, Yehuda G.; Maas, Marielle J P; Kaspers, Gertjan J. L.; Jansen, Gerrit; Cloos, Jacqueline

doi:10.1517/17425255.2015.993316

Cited by 47 publications

(41 citation statements)

References 100 publications

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“…5′ and 3′ splice sites) of cancer genes have been found to promote tumorigenesis by disrupting splicing4142434445. For mutations within core cis -elements, it is straightforward to predict changes in splicing1039.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing

Zhao

Sun

Huang

et al. 2017

Sci Rep

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RBM10 is an RNA splicing regulator that is frequently mutated in lung adenocarcinoma (LUAD) and has recently been proposed to be a cancer gene. How RBM10 mutations observed in LUAD affect its normal functions, however, remains largely unknown. Here integrative analysis of RBM10 mutation and RNA expression data revealed that LUAD-associated RBM10 mutations exhibit a mutational spectrum similar to that of tumor suppressor genes. In addition, this analysis showed that RBM10 mutations identified in LUAD patients lacking canonical oncogenes are associated with significantly reduced RBM10 expression. To systematically investigate RBM10 mutations, we developed an experimental pipeline for elucidating their functional effects. Among six representative LUAD-associated RBM10 mutations, one nonsense and one frameshift mutation caused loss-of-function as expected, whereas four missense mutations differentially affected RBM10-mediated splicing. Importantly, changes in proliferation rates of LUAD-derived cells caused by these RBM10 missense mutants correlated with alterations in RNA splicing of RBM10 target genes. Together, our data implies that RBM10 mutations contribute to LUAD pathogenesis, at least in large part, by deregulating splicing. The methods described in this study should be useful for analyzing mutations in additional cancer-associated RNA splicing regulators.

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Section: Discussionmentioning

confidence: 99%

Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing

Zhao

Sun

Huang

et al. 2017

Sci Rep

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“…Using this strategy the leukemic progenitor cells are also targeted since mutations found in signaling pathways in AML are not limited to the LSC, but are inherited by their progeny. Recent studies have also indicated the relevance of splicing on signaling pathways [61]; therefore, small molecules that affect the spliceosome are also investigated as novel therapeutics to eradicate LSC [62].…”

Section: General Principles and Challenges Faced By Targeting Lscmentioning

confidence: 99%

Leukemic stem cells: identification and clinical application

2017

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“…It has been reported to be overexpressed in metastatic colon cancers relative to primary tumors and normal tissues and to contribute to invasive behavior [38]. Pertaining to mRNA biogenesis and function, HNRPA2B1 [39], EIF4G1, EIF2S2, and ribosomal proteins L12 & L4 all contain highly significant phosphosites as well. Many of the phosphoproteins listed in this table and the specific sites identified would be worth further investigation to tease out the specific mechanistic roles of each site.…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteomics of colon cancer metastasis: comparative mass spectrometric analysis of the isogenic primary and metastatic cell lines SW480 and SW620

2016

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The contributions of phosphorylation-mediated signaling networks to colon cancer metastasis are poorly defined. To interrogate constitutive signaling alterations in cancer progression, the global phosphoproteomes of the patient-matched SW480 (primary colon tumor origin) and SW620 (lymph node metastasis) cell lines were compared with TiO2 and IMAC phosphopeptide enrichment followed by LC-MS/MS. Network analysis of the significantly altered phosphosites revealed differential regulation in cellular adhesion, mitosis, and mRNA translational machinery. mRNA biogenesis and splicing, transport through the nuclear pores, initiating translation, as well as mRNA stability and degradation were also affected. Though alterations in these processes have been associated with oncogenic transformation, control of mRNA stability has typically not been associated with cancer progression. Notably, the single phosphosite with the greatest relative change in SW620 was Ser2 on eukaryotic initiation factor 2 subunit 2 (eIF2S2), suggesting that SW620 cells translate faster or with greater efficiency than SW480 cells. These broad changes in the regulation of translation also occur without over-expression of eukaryotic initiation factor 4E (eIF4E). The findings suggest that metastatic cells exhibit constitutive changes to the phosphoproteome, and that mRNA stability and translational efficiency may be important targets of deregulation during cancer progression.

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Pre-mRNA splicing in cancer: the relevance in oncogenesis, treatment and drug resistance

Cited by 47 publications

References 100 publications

Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing

Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing

Leukemic stem cells: identification and clinical application

Phosphoproteomics of colon cancer metastasis: comparative mass spectrometric analysis of the isogenic primary and metastatic cell lines SW480 and SW620

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