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

• Published in: Cancers Vol. 16; no. 11; p. 2154
• Main Authors: Acha-Sagredo, Amelia, Wilson, Cornelia M, Garcia Bediaga, Naiara, Kalirai, Helen, Davies, Michael P A, Coupland, Sarah E, Field, John K, Liloglou, Triantafillos
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06-06-2024; MDPI
• Subjects: Alternative splicing; Biobanks; Cancer; Cancer therapies; Development and progression; Disease management; DNA methylation; Epidermal growth factor receptors; Epigenetics; Exosomes; Gene expression; Genetic aspects; Genetic transcription; Health aspects; Kinases; Leukocytes; Lung cancer; Lung cancer, Non-small cell; Membrane proteins; Methylation; Non-small cell lung carcinoma; Oncology, Experimental; Small cell lung carcinoma; Tumors; United Kingdom; United Kingdom > UK; non-small cell lung cancer; DNA methylation; sortilin; splicing
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers16112154

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
= 10
). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%,
= 10
) 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.