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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
Published on: April 26, 2017
Abnormal expression of the pre-mRNA splicing regulators SRSF1, SRSF2, SRPK1 and SRPK2 in non small cell lung
Stephanie Gout1, Elisabeth Brambilla, Asma Boudria
1Equipe 2 Bases Moléculaires de la Progression des Cancers du Poumon, INSERM, U823, Grenoble, France.
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.
Insights
SRSF1 and SRSF2 protein overexpression is common in lung cancer, driving aggressive tumor behavior and resistance to chemotherapy, particularly in adenocarcinoma. These splicing factors are key targets for understanding lung tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Splicing abnormalities are frequent in cancer, with SR proteins regulating splice site choice.
- SRSF2 has been implicated in cisplatin-mediated apoptosis in lung carcinoma.
- This study investigates the role of SR proteins SRSF1 and SRSF2 in lung tumorigenesis.
Purpose of the Study:
- To investigate the expression levels of SR proteins SRSF1 and SRSF2 in lung adenocarcinoma (ADC) and squamous cell lung carcinoma (SCC).
- To determine the correlation between SRSF2 phosphorylation and its expression in lung tumors.
- To explore the functional impact of SRSF1 overexpression on lung adenocarcinoma cell invasiveness and therapeutic resistance.
Main Methods:
- Immunohistochemistry was used to assess SRSF1 and SRSF2 protein expression in lung tumors and normal lung tissue.
- Western blotting and kinase assays were employed to analyze protein phosphorylation and kinase upregulation.
- Functional assays, including soft agar growth and Western blotting for marker analysis, were performed in lung adenocarcinoma cell lines.
Main Results:
- SRSF1 and SRSF2 were significantly overexpressed in both ADC and SCC compared to normal lung tissue.
- SRSF2 overexpression correlated with increased phosphorylation in both ADC and SCC.
- SRSF1 overexpression promoted a more invasive phenotype in ADC cells, activating PI3K/AKT and p42/44MAPK pathways and conferring chemoresistance.
- High SRSF1 and phosphorylated SRSF2 levels were associated with advanced stage (III-IV) ADC.
Conclusions:
- Deregulation of pre-mRNA splicing regulators, including SRSF1 and SRSF2, is a common event in lung tumorigenesis.
- The role and outcome of splicing factor deregulation may differ between Non-Small Cell Lung Cancer histological subtypes.
- Overexpression of SRSF1 and SRSF2 contributes to a more aggressive phenotype in lung adenocarcinoma, highlighting their potential as therapeutic targets.
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