实体瘤具有异常高的细胞内[Na]。各种钠通道的活性可能是钠积累的基础。电压门控 Na 通道 (VGSC) 已被证明在癌细胞系中具有功能活性，可促进癌细胞侵袭。然而，所涉及的机制和临床相关性尚不完全清楚。在这里，我们发现 Nav1.5 VGSC 亚型的蛋白表达与乳腺癌患者的转移增加和癌症特异性生存期缩短密切相关。此外，VGSC 在患者来源的乳腺肿瘤细胞、细胞系和癌症相关成纤维细胞中具有功能活性。在乳腺癌小鼠模型中敲除 Nav1.5 可抑制侵袭调节基因的表达。 Nav1.5 活性可能通过上调 Na /K ATP 酶的活性来增加乳腺癌细胞中的 ATP 需求和糖酵解，从而促进 H 的产生和细胞外酸化。鼠异种移植肿瘤的外围 pH 值低于核心区域，即增殖率较高、凋亡率较低的区域。反过来，酸性细胞外 pH 值会增加 Na 通过 Nav1.5 持续流入乳腺癌细胞。总之，这些发现表明细胞外酸化和钠进入癌细胞之间存在正反馈，从而促进侵袭。这些结果强调了 Nav1.5 活性作为乳腺癌转移增强剂的临床意义，并提供了支持在癌症治疗中使用 VGSC 抑制剂的进一步证据。© 2024。作者。

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.© 2024. The Author(s).