Abstract
BackgroundClear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. One of the processes disturbed in this cancer type is alternative splicing, although phenomena underlying these disturbances remain unknown. Alternative splicing consists of selective removal of introns and joining of residual exons of the primary transcript, to produce mRNA molecules of different sequence. Splicing aberrations may lead to tumoral transformation due to synthesis of impaired splice variants with oncogenic potential. In this paper we hypothesized that disturbed alternative splicing in ccRCC may result from improper expression of splicing factors, mediators of splicing reactions.Methodology/Principal FindingsUsing real-time PCR and Western-blot analysis we analyzed expression of seven splicing factors belonging to SR proteins family (SF2/ASF, SC35, SRp20, SRp75, SRp40, SRp55 and 9G8), and one non-SR factor, hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) in 38 pairs of tumor-control ccRCC samples. Moreover, we analyzed splicing patterns of five genes involved in carcinogenesis and partially regulated by analyzed splicing factors: RON, CEACAM1, Rac1, Caspase-9, and GLI1.Conclusions/SignificanceWe found that the mRNA expression of splicing factors was disturbed in tumors when compared to paired controls, similarly as levels of SF2/ASF and hnRNP A1 proteins. The correlation coefficients between expression levels of specific splicing factors were increased in tumor samples. Moreover, alternative splicing of five analyzed genes was also disturbed in ccRCC samples and splicing pattern of two of them, Caspase-9 and CEACAM1 correlated with expression of SF2/ASF in tumors. We conclude that disturbed expression of splicing factors in ccRCC may possibly lead to impaired alternative splicing of genes regulating tumor growth and this way contribute to the process of carcinogenesis.
Highlights
Renal cell carcinoma (RCC) is the most common solid lesion of the kidney and represents,3% of all human malignancies
The mRNA expression of splicing factors is disturbed in at least half of Clear cell renal cell carcinoma (ccRCC) samples Splicing factors belonging to the group of SR proteins comprise a large number of structurally and functionally related proteins [11]
In our study we focused on the group of ‘‘classical’’ SR proteins, i.e. SF2/ASF, SC35 (SFRS2), Sp20 (SFRS3), SRp75 (SFRS4), SRp40 (SFRS5), SRp55 (SFRS6), and 9G8 (SFRS7)
Summary
Renal cell carcinoma (RCC) is the most common solid lesion of the kidney and represents ,3% of all human malignancies. The vast majority (80%) of RCC cases are histologically classified as clear cell renal cell carcinomas (ccRCC), originating from proximal tubules of the kidney. One of the cellular processes, often disturbed in cancers, is alternative splicing, the process of selective removal of introns and joining of residual exons, in which mRNA molecules of various sequences are produced. Several other reports showing ccRCC-specific disturbances of alternative splicing include alterations in mRNA processing of Mcl-1 [7], TCF-4 [8], survivin [9], and OGG1 [10]. Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. Alternative splicing consists of selective removal of introns and joining of residual exons of the primary transcript, to produce mRNA molecules of different sequence. Splicing aberrations may lead to tumoral transformation due to synthesis of impaired splice variants with oncogenic potential. In this paper we hypothesized that disturbed alternative splicing in ccRCC may result from improper expression of splicing factors, mediators of splicing reactions
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