Abstract
Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability.
Highlights
SRSF2 is a member of SR family of proteins that regulate constitutive and alternative splicing by binding to the sequences of splicing enhancers and influencing exon inclusion [1]
According to qPCR analysis, the mean expression of SRSF2 mRNA was moderately decreased (p = 0.0005) in Clear cell renal cell carcinoma (ccRCC) tumour samples when compared with controls (Figure S1)
SRSF2 mRNA expression was decreased in tumour samples by 1.68-fold when compared with non-tumourous control samples (p = 1.23 × 10−18)
Summary
SRSF2 is a member of SR family of proteins that regulate constitutive and alternative splicing by binding to the sequences of splicing enhancers and influencing exon inclusion [1]. By interacting with transcription factor E2F1, SRSF2 stimulates its activity toward the gene-regulating cell cycle [2]. Proapoptotic proteins of the BCL2 family induce permeabilization of the outer mitochondrial membrane and the release of cytochrome c that leads to activation of caspase-9. Both pathways finalize in the cleavage of cellular proteins and culminate in cell shrinkage, chromatin breakdown, and changes in plasma membrane structure [14]. For the first time, that decreased expression of SRSF2 in ccRCC results in widespread alterations in the expression of apoptotic regulators and leads to inhibition of apoptosis
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