Abstract
Voltage-gated sodium channel β subunits (encoded by SCN1B to SCN4B genes) have been demonstrated as important multifunctional signaling molecules modulating cellular processes such as cell adhesion and cell migration. In this study, we aimed to explore the expression profiles of SCN4B in papillary thyroid cancer (PTC) and its prognostic value in terms of recurrence-free survival (RFS) in classical PTC. In addition, we also examined the potential effect of DNA methylation on its expression. A retrospective study was performed by using data from available large databases, including the Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA)-Thyroid Cancer (THCA). Results showed that SCN4B is downregulated at both RNA and protein level in PTC compared with normal thyroid tissues. Preserved SCN4B expression was an independent indicator of favorable RFS in patients with classical PTC, no matter as categorical variables (HR: 0.243, 95%CI: 0.107–0.551, p = 0.001) or as a continuous variable (HR: 0.684, 95%CI: 0.520–0.899, p = 0.007). The methylation status of one CpG site (Chr11: 118,022,316–318) in SCN4B DNA had a moderately negative correlation with SCN4B expression in all PTC cases (Pearson’s r = -0.48) and in classical PTC cases (Pearson’s r = -0.41). In comparison, SCN4B DNA copy number alterations (CNAs) were not frequent and might not influence its mRNA expression. In addition, no somatic mutation was found in SCN4B DNA. Based on these findings, we infer that preserved SCN4B expression might independently predict favorable RFS in classical PTC. Its expression might be suppressed by DNA hypermethylation, but is less likely to be influenced by DNA CNAs/mutations.
Highlights
Voltage-gated sodium channels are integral membrane proteins that constitute one large poreforming principal α subunit and one or two smaller transmembrane β subunits as auxiliary [1, 2]
SCN4B was downregulated in papillary thyroid cancer (PTC) compared with normal thyroid tissues
The heatmap of the array results showed that SCN4B was one of the most downregulated sodium channel subunits in PTC compared with normal thyroid tissues (Fig 1A, red dotted frame)
Summary
Voltage-gated sodium channels are integral membrane proteins that constitute one large poreforming principal α subunit and one or two smaller transmembrane β subunits as auxiliary (encoded by SCN1B to SCN4B genes) [1, 2]. SCN4B expression and RFS in classical PTC auxiliary subunits modulating the gating, kinetics, and localization of the ion channel pore, there are emerging studies showed that they are important multifunctional signaling molecules regulating cell adhesion, cell migration, differentiation, endosome acidification, phagocytosis and podosome formation, with or without the presence of pore-forming α subunit [2, 3]. In breast cancer cells, decreased SCN4B protein expression correlates with high-grade primary and metastatic breast tumors and is associated with enhanced breast cancer cell migration, invasiveness and metastatic spreading [6]
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