[Disturbances of alternative splicing in cancer]. / Zaburzenia róznicowego skladania pierwotnego transkryptu w kancerogenezie.

Splicing of pre-mRNA is one of the post-transcriptional modifications in which introns are removed from primary transcript and exons are joined. pre-mRNA splicing reactions are catalyzed by dynamic complex called spliceosome. Exons can be joined on different manners in a process known as alternative splicing, that provide production of multiple mRNA and protein isoforms from relatively low number of genes. Alternative splicing is regulated by cis elements localized within exons or introns and trans-acting factors including spliceosome components and members of the SR and hnRNP protein family that exert antagonistic effects on splicing. Aberrant pre-mRNA splicing may be caused by mutations in cis elements and altered expression of splicing factors. This review describes disturbances in splicing of genes controlling proliferation and metastasis that can lead to tumoral transformation. Also, potential applications of abnormally spliced transcripts that may potentially serve as diagnostic biomarkers of cancer or targets in anticancer therapy are discussed.

Disturbed expression of splicing factors in renal cancer affects alternative splicing of apoptosis regulators, oncogenes, and tumor suppressors.

BACKGROUND: Clear 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 FINDINGS: Using 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/SIGNIFICANCE: We 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.