Inserm UMR1069, Nutrition, Croissance et Cancer, Université François-Rabelais de Tours, 10 Boulevard Tonnellé, 37032 Tours, France.
Inflammation and Experimental Surgery Unit, CIBERehd, Murcia's BioHealth Research Institute IMIB-Arrixaca, Clinical University Hospital Virgen de la Arrixaca, E-30120 Murcia, Spain.
Nat Commun. 2016 Dec 5;7:13648. doi: 10.1038/ncomms13648.
The development of metastases largely relies on the capacity of cancer cells to invade extracellular matrices (ECM) using two invasion modes termed 'mesenchymal' and 'amoeboid', with possible transitions between these modes. Here we show that the SCN4B gene, encoding for the β4 protein, initially characterized as an auxiliary subunit of voltage-gated sodium channels (Na) in excitable tissues, is expressed in normal epithelial cells and that reduced β4 protein levels in breast cancer biopsies correlate with high-grade primary and metastatic tumours. In cancer cells, reducing β4 expression increases RhoA activity, potentiates cell migration and invasiveness, primary tumour growth and metastatic spreading, by promoting the acquisition of an amoeboid-mesenchymal hybrid phenotype. This hyperactivated migration is independent of Na and is prevented by overexpression of the intracellular C-terminus of β4. Conversely, SCN4B overexpression reduces cancer cell invasiveness and tumour progression, indicating that SCN4B/β4 represents a metastasis-suppressor gene.
转移的发展在很大程度上依赖于癌细胞利用两种侵袭模式（间质和阿米巴样）侵袭细胞外基质（ECM）的能力，这两种模式之间可能存在转换。在这里，我们表明编码β4 蛋白的 SCN4B 基因最初被表征为兴奋性组织中电压门控钠离子通道（Na）的辅助亚基，在正常上皮细胞中表达，并且乳腺癌活检中β4 蛋白水平降低与高级原发性和转移性肿瘤相关。在癌细胞中，降低β4 表达会增加 RhoA 活性，通过促进获得阿米巴样-间质混合表型，增强细胞迁移和侵袭性、原发性肿瘤生长和转移扩散。这种超激活的迁移不依赖于 Na，并可通过β4 的胞内 C 端的过表达来预防。相反，SCN4B 的过表达降低了癌细胞的侵袭性和肿瘤进展，表明 SCN4B/β4 代表一种转移抑制基因。
