Abstract
Splicing abnormalities frequently occur in cancer. A key role as splice site choice regulator is played by the members of the SR (Ser/Arg-rich) family of proteins. We recently demonstrated that SRSF2 is involved in cisplatin-mediated apoptosis of human lung carcinoma cell lines. In this study, by using immunohistochemistry, we demonstrate that the SR proteins SRSF1 and SRSF2 are overexpressed in 63% and 65% of lung adenocarcinoma (ADC) as well as in 68% and 91% of squamous cell lung carcinoma (SCC), respectively, compared to normal lung epithelial cells. In addition, we show that SRSF2 overexpression correlates with high level of phosphorylated SRSF2 in both ADC (p<0.0001) and SCC (p = 0.02), indicating that SRSF2 mostly accumulates under a phosphorylated form in lung tumors. Consistently, we further show that the SR-phosphorylating kinases SRPK1 and SRPK2 are upregulated in 92% and 94% of ADC as well as in 72% and 68% of SCC, respectively. P-SRSF2 and SRPK2 scores are correlated in ADC (p = 0.01). Using lung adenocarcinoma cell lines, we demonstrate that SRSF1 overexpression leads to a more invasive phenotype, evidenced by activation of PI3K/AKT and p42/44MAPK signaling pathways, increased growth capacity in soft agar, acquisition of mesenchymal markers such as E cadherin loss, vimentin and fibronectin gain, and increased resistance to chemotherapies. Finally, we provide evidence that high levels of SRSF1 and P-SRSF2 proteins are associated with extensive stage (III-IV) in ADC. Taken together, these results indicate that a global deregulation of pre-mRNA splicing regulators occurs during lung tumorigenesis and does not predict same outcome in both Non Small Cell Lung Carcinoma histological sub-types, likely contributing to a more aggressive phenotype in adenocarcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Aged
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Antineoplastic Agents / pharmacology
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Carboplatin / pharmacology
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology
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Carcinoma, Squamous Cell / metabolism*
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Female
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Humans
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Lung / metabolism
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Male
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Middle Aged
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Neoplasm Staging
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Paclitaxel / pharmacology
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism*
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism*
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Serine-Arginine Splicing Factors
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Signal Transduction
Substances
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Antineoplastic Agents
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Nuclear Proteins
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Phosphoproteins
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RNA-Binding Proteins
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Ribonucleoproteins
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SRSF2 protein, human
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Serine-Arginine Splicing Factors
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Carboplatin
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SRPK1 protein, human
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Protein Serine-Threonine Kinases
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SRPK2 protein, human
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Paclitaxel
Grants and funding
This work was supported by the Ligue Nationale contre le Cancer (Equipe Labellisée Ligue 2007), by the Comité Départemental Isère and Comité Départemental Savoie de la Ligue Nationale contre le Cancer, by the Institut National du Cancer/Direction de l’Hospitalisation et Organisation des Soins (INca/DHOS) (Appel d’Offre Recherche Translationnelle 2010), by the Fondation de France (Projet Grande Ampleur) and by the Association pour la Recherche Contre le Cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.