Table 1.

Expression and identified roles of pore-forming Na_Vα and auxiliary Na_Vβ in cancer

Isoform	Expression levels	Cancer type	Role in cancer, proposed mechanism	References
NaV1.1	Upregulateda (mRNA, protein)	Lymph nodes from CRC	Unknown, unknown	Lin et al. (2019)
NaV1.2	Upregulateda (Protein)	Liver	Unknown, unknown	The Human protein Atlas (www.proteinatlas.org)
NaV1.3	Upregulateda (mRNA)	Ovarian	Unknown, unknown	Gao et al. (2010)
NaV1.4	Upregulateda (mRNA)	Cervix	Unknown, unknown	Diaz et al. (2007)
NaV1.5	Upregulateda,b (mRNA, protein, INa+)	Breast	↑Invasionc,d ▪ Through an increased Src kinase activity promoting invadopodial formation and favoring an allosteric activation of NHE-1, extracellular acidification and enhanced activity of cysteine−cathepsins proteases ▪ Boosting the EMT transition via SIK1 ▪ Generating a sustained plasma membrane depolarization that leads to Rac1 activation and cytoskeleton reorganization ▪ Increasing MMP9 expression and reducing apoptosis	Roger et al. (2003), Fraser et al. (2005), Brackenbury et al. (2007), Gillet et al. (2009), Brisson et al. (2011), Yang et al. (2012), Brisson et al. (2013), Driffort et al. (2014), Nelson et al. (2015a),b, Gradek et al. (2019), Yang et al. (2020),
		Colorectal	↑Invasionc Through the regulation of the transcriptional pathway PKA/ERK/c-jun/ELK-1/ETS-1	House et al. (2010), Baptista-Hon et al. (2014), House et al. (2015), Guzel et al. (2019), Poisson et al. (2020)
		Ovarian	↑Migrationc ↑Invasionc ↑Proliferationc ▪ By increasing the window current and depolarization of resting potential	Gao et al. (2010), Liu et al. (2018)
		Leukemia	↑Invasionc ▪ Endosomal acidification and enhanced phagocytosis via calcium signaling	Fraser et al. (2004), Carrithers et al. (2007), Carrithers et al., 2012, Rahgozar et al. (2013), Jones et al. (2014), Huang et al. (2015)
NaV1.6	Upregulateda,b (mRNA, protein, INa+)	Cervix	↑Invasionc ▪ Boosted activity of MMP2 and NHE-1	Diaz et al. (2007), Hernandez-Plata et al. (2012), Lopez-Charcas et al. (2018)
		Leukemia	↑Invasionc ▪ Invadopodial formation and enhanced activity	Carrithers et al. (2009)
		Melanoma	↑Invasionc ▪ Invadopodial formation and enhanced activity	Carrithers et al. (2009)
		Lymph nodes from CRC	Unknown, unknown	Lin et al. (2019)
	Downregulateda,b (mRNA, protein, INa+)	Erwin sarcoma	↓Migrationc ↑Apoptosisc Through a repression of SCN8A by RING1B and maintaining low NF-κβ levels	Hernandez-Munoz et al. (2016)
		Colorectal	Unknown, unknown	Igci et al. (2015)
NaV1.7	Upregulateda,b (mRNA, protein, INa+)	Prostate	↑Invasionc,d ▪ Cell motility increased via galvanotaxis	Grimes et al. (1995), Diss et al. (2001), Diss et al. (2005), Yildirim et al. (2012), Bugan et al. (2019)
		Lung (NSCLC)	↑Invasionc ▪ Dysregulation of sodium homeostasis ▪ Increase of [NA+]i and depolarization of cell membrane	Roger et al. (2007) Campbell et al. (2013)
		Lung (SCLC)	Unknown Participation in the formation of a neuroendocrine-like tumor cell phenotype	Pancrazio et al. (1989), Blandino et al. (1995), Onganer et al. (2005)
		Stomach	↑Invasionc,d ↑Tumor growthd ▪ Cancer progression through MACC1-mediated upregulation of NHE-1	Xia et al. (2016)
		Endometrial	↑Invasionc,d↑Tumor growthd↓Apoptosisd ▪Unknown	Liu et al. (2018), Liu et al. (2019)
	Downregulateda (mRNA, protein)	Colorectal	Unknown, unknown ▪ Proposed within a risk score with high prognostic value for overall survival	Pan et al. (2017)
NaV1.8	Upregulatedb (mRNA)	Lung (NSCLC)	Unknown, unknown	Roger et al. (2007)
NaV1.9	Upregulatedb (mRNA)	Lung (NSCLC)	Unknown, unknown	Roger et al. (2007)
NaVβ1	Upregulateda,b (mRNA, protein)	Prostate	Unknown, unknown	Diss et al. (2008)
		Breast	↑Tumor growthc,d ↑Vascularizationd ↑Invasionc ↓Apoptosis ▪ β1 trans-homophilic adhesion triggering of cell process outgrowth via Fyn kinase	Nelson et al. (2014), Bon et al. (2016)
	Downregulatedb (mRNA, protein)	Breast	↑Invasionc By decreasing cell adhesion and facilitating cell migration	Chioni et al. (2009)
		Lung	↑Invasionc By decreasing cell adhesion	Campbell et al. (2013)
		Cervix	↑Migrationc ▪Acting as a cell adhesion molecule ↓Proliferationc ▪By increasing the population of cells in the G0/G1 phase in cell cycle	Sanchez-Sandoval and Gomora (2019)
NaVβ2	Upregulatedb (mRNA, protein)	Prostate	↑Invasionc ▪ Promotion of bipolar cell morphology, enhanced cell adhesion and motility through association with neural substrates. ↓Tumor volume in xenograft models‡	Jansson et al. (2012), Jansson et al. (2014)
NaVβ3	Upregulatedb (mRNA, protein)	Bone	↑Apoptosisc ▪ Increase of a p53-dependent apoptotic pathway	Adachi et al. (2004)
NaVβ4	Downregulateda,b (mRNA, protein)	Breast	↑Invasionc,d ▪ Enhanced RhoA activity ▪ Mediated by the intracellular C-terminus motif ▪ Acquisition of a hybrid mesenchymal-amoeboid aggressive phenotype	Bon et al. (2016)
		Lung	Unknown, unknown	Bon et al. (2016)
		Cervix	↑Invasionc	Sanchez-Sandoval and Gomora (2019)
		Thyroid	Unknown ▪ Its expression is an indicator of favorable recurrence-free survival	Gong et al. (2018)

^aCancer tissue versus non-cancerous tissue.

^bHighly invasive cell line versus normal immortalized cell line.

^cIn vitro.

^dIn vivo.