Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

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.

BCL-w: apoptotic and non-apoptotic role in health and disease

“…Upstream sequence element (USE) in the 3'-UTR of BCL-w transcript contributed to 3'-end formation via interaction with splicing factors: U2 small nuclear RNA auxiliary factor 1 (U2AF35), U2 small nuclear RNA auxiliary factor 2 (U2AF65) and heterogeneous nuclear ribonucleoprotein I (hnRNPI) 52 . In addition, downregulation of serine and arginine-rich splicing factor 2 (SRSF2) was associated with decreased BCL-w transcript level 53 . It was also demonstrated that multiple copies in T-cell lymphoma-1 (MCT-1) protein Table 1.…”

Renal Cell Tumors: Understanding Their Molecular Pathological Epidemiology and the 2016 WHO Classification

“…Renal cell tumors represent a group of histopathologically and molecularly heterogeneous tumors, with different sets of genetic and epigenetic abnormalities [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. An increased understanding of the morphology, immunohistochemistry, genomics, and epidemiology of renal cell tumors has resulted in the identification of novel features in their molecular pathological epidemiology.…”

Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

“…Renal cell carcinoma (RCC) represents a group of molecularly heterogeneous diseases characterized by differing sets of genetic and epigenetic abnormalities [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) is an RCC subtype characterized by early onset.…”