Sodium channels in endometrial cancer (EC) have been less studied. In EC biopsies, Na_V1.7 is overexpressed in 75% of samples analyzed, compared to adjacent non-cancerous tissue. A higher expression was also correlated with tumor size and local lymph node metastasis (LNM) and associated with poor prognosis. The role of Nav1.7 in EC was analyzed by activating the channel with veratridine, resulting in decreased cell apoptosis and increased cell invasion, while blocking the channel with PF-05089771 generated apoptosis and decreased invasion [42]. These results strongly suggest Na_V1.7 channels as potential EC biomarkers and targets. The clearly identified tumor-promoting role of these channels can be exploited in personalized medicine.

Na_V channels are upregulated in OC cells, predominantly Na_V1.1, Na_V1.3, Na_V1.4, and Na_V1.5, compared to normal ovaries. Blocking Na_V channels with 30 µM of tetrodotoxin reduces migration and invasion in Caov-3 and SK-OV-3 cell lines. In patient samples with OC with LNM, Na_V1.5 mRNA expression level is higher compared to the normal ovary and ovarian cancer without LNM. In accordance, Na_V1.5 protein expression was found in OC with LNM but not in the normal ovary [43]. Furthermore, blocking Na_V1.5 channels with eicosapentaenoic acid (EPA) diminishes cell migration and proliferation in the SK-OV-3 cell line in a dose-dependent manner by increasing the inactivation of the channel [44]. In cancer cells, Na_V α and β subunits regulate migration, invasion, and metastasis. Data analysis of SCNN1A (sodium channel epithelial 1 subunit alpha) levels in OC patients shows a higher channel expression compared to normal ovary samples, and this correlates with a poorer overall survival. Channel overexpression was also observed in SK-OV-3, HO-8910, OVCAR-3, and CoC1 cell lines by RT-qPCR using the normal ovary cell line IOSE80 as a control. Accordingly, knockout of the SCNN1A reduced cell migration and invasion in SK-OV-3 cells; these effects were explained in part by their participation in the epithelial-to-mesenchymal transition (EMT), since SCNN1A silencing promotes the expression of E-cadherin, and reduces the expression of vimentin, N-cadherin, and Snail proteins [45]. This is consistent with Nav α subunits, where they also participate by promoting metastasis characteristic in breast and prostate cancer [46]. In the case of Na_V β subunits, RNA sequencing analysis revealed Nav channel expression in 48 ovarian cancer cell lines, showing a reduced expression of SCN8A (Na_V1.6) and SCN1B (sodium voltage-gated channel beta subunit 1) in cancer cells. Furthermore, microarray analysis of OC tumors from patients showed a higher overall survival (OS) in patients that express lower levels of SCN8A, and poorer OS with lower levels of SCN1B [47]. SCN1B has been linked to tumor growth, metastasis, and vascularization in a xenograft model of breast cancer [48]. These observations suggest that the analysis of Nav channel expression may lead to improved clinical management of OC patients. In addition, these observations suggest that the association of sodium channels with cancer involves different molecular mechanisms, depending on the type of sodium channel and may include non-conducting functions via Na_V β subunit-mediated adhesion. This differential participation supports the precise characterization of the sodium channel expression pattern in OC patients to improve personalized medicine.

In HPV16- positive cervical cancer (CCa) biopsies and in cervical cancer primary cell cultures, Na_V1.6 and Nav1.7b mRNA overexpression was found when compared to non-cancerous biopsies; although protein expression was found in CCa and non-cancerous samples by immunohistochemistry, the pattern of positive cells was more widely distributed in all the sections of squamous epithelial tissue in CCa biopsies [49]. Na_V1.6 expression was related to increased invasive capacity in CCa cells, and protein expression was more abundant in CCa than in noncancerous biopsies [50]. On the contrary, overexpression of ENaC in CCa can be a better prognosis marker. RNA sequencing data from human CCa, showed a better outcome when SCNN1A, SCNN1B, and SCNN1G are simultaneously overexpressed; interestingly, a higher expression was observed in normal tissues and in low-grade CCa patients [51]. Therefore, ENaC channels comprise potential biomarkers for a better prognosis in CCa patients [51]. Because CCa is associated not only with HPV infection, but with other factors, including hormone use and smoking, it would be very interesting to perform preclinical studies concerning the regulation of sodium channels by CCa risk factors. In addition, epidemiological studies analyzing sodium channel expression in smokers or hormone using CCa patients is deserved.

In addition, the regulation of sodium channel expression in normal excitable cells should be studied. How are these channels regulated in such a manner that cell proliferation is controlled? Because sodium fluxes change the membrane potential, studying the regulation of membrane potential by cancer-associated factors (and vice-versa) will provide relevant insights into cancer development.