Nav1.6 drives colorectal cancer proliferation and invasion through MAPK signaling pathway.

Background: Voltage-gated sodium channels (VGSCs, or Navs) are highly expressed in various tumors and play a critical role in tumor metastasis and invasion.

Aim: To identify Nav1.6-associated cancer genes through bioinformatics analysis and experimental validation, with the goal of determining the role of Nav1.6 in colorectal cancer (CRC) metastasis.

Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data were analyzed using weighted correlation network analysis (WGCNA) and Venn analysis to identify Nav1.6-associated genes in CRC. siRNA, real-time PCR, and western blotting were employed to validate the Nav1.6-associated cancer genes and signaling pathways identified in CRC. Cell counting kit-8 and Transwell migration assays were used to assess the proliferation and migration of CRC cells.

Results: The analysis of TCGA and GEO datasets, along with WGCNA, identified 575 differentially expressed genes associated with SCN8A (Nav1.6) in CRC, which were particularly enriched in MAPK signaling pathways. Tissue microarray analysis of surgical samples revealed elevated Nav1.6 levels in CRC tissues, which were predominantly in the cytoplasm and nucleus rather than in the membrane. Cytoplasmic Nav1.6 expression increased with T stage increases, consistent with the TCGA findings. SCN8A knockdown in colon tumor cells significantly reduced cell proliferation and invasion and downregulated key proteins in the RAF-MAPK pathway.

Conclusion: These findings suggest that Nav1.6 promotes CRC cell proliferation and invasion which is related to the MAPK signaling pathway.