Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Simple Summary: Sortilin is a protein with tumour-suppressor activity. Among other functions, sortilin moves around other proteins in the cell and also out of it by leading them to small vesicles termed exosomes. The aim of this study was to establish the degree of abnormal expression of the gene in non-small cell lung cancer. We show here that the alternative forms of the gene are affected both qualitatively and quantitatively. In addition, the ratio of their expression changes. We demonstrate that expression changes of the SORT1 form are due to DNA methylation of its regulatory region. As sortilin is involved in trafficking EGFR, a known target of current drugs, it is possible that these alterations, beyond their involvement in cancer development, may be predictive of the response to these therapies. Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann–Whitney test p = 10 −6 ). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10 −15 ) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management. [ABSTRACT FROM AUTHOR]

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