Splicing findings offer lung cancer clues

Researchers from Spain have identified several new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer, suggesting that their dysregulation is involved in the pathogenesis of the disease.

The study, published in Cancer Research, revealed four genes – ATP11C, IQCB1, TUBD1, and PRRC2C – with a significantly different pattern of splicing in primary non-small-cell lung tumors compared with healthy tissue.

Luis Montuenga (Center for Applied Medical Research, Pamplona) and colleagues developed the ExonPointer algorithm to identify genome-wide differential splicing events in a lung adenocarcinoma cell line after downregulation of the oncogenic SRSF1(serine/arginine-rich splicing factor 1) using short interfering (si)RNA.

Using two exon-junction microarray platforms, the team identified cassette events – in which an exon is either retained or spliced out of the transcript – and ranked them with the ExonPointer algorithm. Then, using polymerase chain reaction, 60% and 100%, respectively, of the top 20 events for each platform were validated. Additionally, the researchers further validated their results using four other lung cancer cell lines.

To assess the clinical relevance of their findings, Montuenga et al tested the presence of the identified splicing events in stored tumor tissue from lung cancer patients. Compared with healthy lung tissue, SRSF1 was overexpressed and there was significant dysregulation in the splicing of four genes – ATP11C, IQCB1, TUBD1, and PRRC2C.

And, the team showed that, in the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon, resulting in overexpression of a PRRC2C variant in primary lung tumors. And, siRNA downregulation of the exon-containing variant significantly reduced cell growth, demonstrating the proliferative effect of the splicing event.

Montuenga et al note that PRRC2C has previously been linked to cancer and to roles in proliferation and cell cycle regulation, however none of the four molecules has previously been associated with lung cancer.

The authors conclude that their findings support the use of technologies such as theirs.

“[E]xon-junction microarrays, together with the appropriate algorithm, provide a reliable analytical tool for genome-wide examination of differential alternative splicing in a time and cost effective manner,” they write.

The team adds: “The use of this technology in other experimental and biological conditions would provide valuable information on the implication of alternative splicing in normal and pathological human biology.”

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