Abstract
Voltage-gated sodium (NaV) channels have been related with cell migration and invasiveness in human cancers. We previously reported the contribution of NaV1.6 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 NaV1.6 gene (SCN8A) overexpression is a general characteristic of CeCa, regardless of the HPV type. In contrast, no differences were observed in NaV1.6 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 NaV1.6 channel, whereas the full-length adult form was present in CeCa biopsies. Correlatively, patch-clamp experiments showed no evidence of whole-cell sodium currents (INa) in CeCa cell lines. Heterologous expression of full-length NaV1.6 isoform in C33A cells produced INa, which were sufficient to significantly increase invasion capacity and matrix metalloproteinase type 2 (MMP-2) activity. These data suggest that upregulation of NaV1.6 channel expression occurs when cervical epithelium have been transformed into cancer cells, and that NaV1.6-mediated invasiveness of CeCa cells involves MMP-2 activity. Thus, our findings support the notion about using NaV channels as therapeutic targets against cancer metastasis.
Highlights
The expression analysis indicated an upregulation of SCN8A gene in the invasive cervical cancer (CeCa) samples regardless of the oncogenic human papillomavirus (HPV) type, such change was not observed in low- and high-grade cervical intraepithelial neoplasia (Fig. 1A,B and Supplementary Fig. S2), supporting the idea that SCN8A overexpression is associated with oncogenic transformation
Receiver Operating Characteristic (ROC) analysis indicated that is possible to discriminate between non-cancerous samples from those of invasive cervical cancer with a higher sensitivity (~98%; Supplementary Fig. S4), than the 55% reported for the pap smear test[35], meaning that SCN8A gene levels could be more effective in identifying true positive cases that the typical pap smear test
All these results were obtained by using biopsies positives to HPV-16, the most frequent viral type detected in CeCa, accounting for approximately 50% of all cases; at least eight more high-risk types of HPVs (18, 58, 33, 45, 31, 52 and 35) account for an additional 40% of CeCa cases[1,48]
Summary
The loss of SCN4B in human breast cancer cells, gene that encodes for the NaVβ4 subunit of VGSCs, promotes the acquisition of an amoeboid-mesenchymal hybrid phenotype associated with metastases, while its overexpression reduces cancer cell invasiveness[22], demonstrating new non-canonical functions for the auxiliary NaVβ subunits in addition to those shown for the pore-forming α-subunits of NaVs. In addition, a recent study showed that NaV1.7 channels encoded by the SCN9A gene is abundantly expressed in human gastric cancer where its activity induced an increase in NHE-1 expression, proliferation, invasion, and expression of the oncoprotein metastasis-associated in colon cancer-1 (MACC1)[10]. The activity of this sodium channel contributes to the cellular invasion through its effects on podosome and invadopodia formation via a mechanism involving intracellular movement of sodium and calcium ions as well as F-actin cytoskeletal remodeling in these cells[23]
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