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The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+\/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming \u03b1-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.<\/jats:p>","DOI":"10.3390\/cancers15010046","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T03:24:30Z","timestamp":1671679470000},"page":"46","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Voltage-Gated Sodium Channel NaV1.5 Controls NHE\u22121\u2212Dependent Invasive Properties in Colon Cancer Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5080-8310","authenticated-orcid":false,"given":"Osbaldo","family":"Lopez-Charcas","sequence":"first","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Poisson","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1530-6953","authenticated-orcid":false,"given":"Oumnia","family":"Benouna","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-3614","authenticated-orcid":false,"given":"Roxane","family":"Lemoine","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Chadet","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"P\u00e9tereau","sequence":"additional","affiliation":[{"name":"Service D\u2019anatomie et de Cytologie Pathologiques, H\u00f4pital Trousseau, CHU de Tours, 37170 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Widad","family":"Lahlou","sequence":"additional","affiliation":[{"name":"Service D\u2019h\u00e9pato-Gastroent\u00e9rologie et de Canc\u00e9rologie Digestive, H\u00f4pital Trousseau, CHU de Tours, 37170 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2783-9722","authenticated-orcid":false,"given":"Serge","family":"Guy\u00e9tant","sequence":"additional","affiliation":[{"name":"Service D\u2019anatomie et de Cytologie Pathologiques, H\u00f4pital Trousseau, CHU de Tours, 37170 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehdi","family":"Ouaissi","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, France"},{"name":"Service de Chirurgie Visc\u00e9rale et Oncologique, H\u00f4pital Trousseau, CHU de Tours, 37170 Tours, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0726-3060","authenticated-orcid":false,"given":"Piyasuda","family":"Pukkanasut","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-1240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilpa","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-1240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0342-2378","authenticated-orcid":false,"given":"Sadanandan","family":"Velu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-1240, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1257-8005","authenticated-orcid":false,"given":"Pierre","family":"Besson","sequence":"additional","affiliation":[{"name":"EA4245, Transplantation, Immunologie et Inflammation, Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Tours, 37032 Tours, 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