Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer.
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, andTP53. We also identified a new splice variant ofCFLAR, 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.
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. hanna.kedzierska@cmkp.edu.pl.
Hanna
H
Kędzierska
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. piotrp@cmkp.edu.pl.
Piotr
P
Popławski
Laboratory of Flow Cytometry, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. grazyna.hoser@cmkp.edu.pl.
Grażyna
G
Hoser
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. beata.rybicka@cmkp.edu.pl.
Beata
B
Rybicka
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. katarzyna.rodzik@cmkp.edu.pl.
Katarzyna
K
Rodzik
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. elzbieta.sokol@cmkp.edu.pl.
Elżbieta
E
Sokół
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. lampkojo@cmkp.edu.pl.
Joanna
J
Bogusławska
Department of Urology, Regional Hospital, 07-410 Ostrołęka, Poland. tanska@interia.pl.
Zbigniew
Z
Tański
Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland. annaFogtman@ibb.waw.pl.
Anna
A
Fogtman
Laboratory for Microarray Analysis, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland. marta@ibb.waw.pl.|Laboratory of Systems Biology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland. marta@ibb.waw.pl.
Marta
M
Koblowska
Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland. apiekielko@cmkp.edu.pl.
Agnieszka
A
Piekiełko-Witkowska
CFLAR; SRSF2; TCGA; alternative splicing; apoptosis; caspase-9; ccRCC; mRNA; renal cancer
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