The invasiveness of human cervical cancer associated to the function of Na(V)1.6 channels is mediated by MMP-2 activity

Voltage-gated sodium (Na(V)) channels have been related with cell migration and invasiveness in human cancers. We previously reported the contribution of Na(V)1.6 channels activity with the invasion capacity of cervical cancer (CeCa) positive to Human Papilloma Virus type 16 (HPV16), which accounts for 50% of all CeCa cases. Here, we show that Na(V)1.6 gene (SCN8A) overexpression is a general characteristic of CeCa, regardless of the HPV type. In contrast, no differences were observed in Na(V)1.6 channel expression between samples of non-cancerous and cervical intraepithelial neoplasia. Additionally, we found that CeCa cell lines, C33A, SiHa, CaSki and HeLa, express mainly the splice variant of SCN8A that lacks exon 18, shown to encode for an intracellularly localized Na(V)1.6 channel, whereas the full-length adult form was present in CeCa biopsies. Correlatively, patch-clamp experiments showed no evidence of whole-cell sodium currents (I(Na)) in CeCa cell lines. Heterologous expression of full-length Na(V)1.6 isoform in C33A cells produced I(Na), which were sufficient to significantly increase invasion capacity and matrix metalloproteinase type 2 (MMP-2) activity. These data suggest that upregulation of Na(V)1.6 channel expression occurs when cervical epithelium have been transformed into cancer cells, and that Na(V)1.6-mediated invasiveness of CeCa cells involves MMP-2 activity. Thus, our findings support the notion about using Na(V) channels as therapeutic targets against cancer metastasis.