Dulong C, Fang Y J, Gest C, Zhou M H, Patte-Mensah C, Mensah-Nyagan A G, Vannier J P, Lu H, Soria C, Cazin L, Mei Y A, Varin R, Li H
MERCI, EA 3829, Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France.
Center for Brain Science Research, School of Life Science, Fudan University, P.R. China.
Int J Oncol. 2014 Feb;44(2):539-47. doi: 10.3892/ijo.2013.2214. Epub 2013 Dec 10.
Voltage-gated Na+ channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels.
电压门控钠通道（VGSCs）在包括乳腺癌、前列腺癌和肺癌在内的多种类型癌症以及间皮瘤和宫颈癌中高度表达。尽管VGSCs的活性被认为对癌细胞迁移和侵袭的增强至关重要，但其在癌细胞中功能表达和调节的机制仍不清楚。在本研究中，研究了小GTP酶RhoA在乳腺癌细胞系MDA-MB 231和MCF-7中对Nav1.5通道表达和功能调节中的作用。RhoA沉默显著降低了Nav1.5通道表达和钠电流，表明RhoA对癌细胞中活性形式的Nav1.5通道合成发挥刺激作用。抑制Nav1.5表达显著降低了细胞侵袭和增殖。此外，观察到Nav1.5沉默诱导的RhoA蛋白水平下降。总之，这些发现揭示了：i）小GTP酶RhoA在Nav1.5通道表达上调和肿瘤侵袭性中的关键作用，以及ii）Nav1.5通道对RhoA蛋白水平存在正反馈。
