Expression of voltage-gated sodium channel α subunit in human ovarian cancer

Abstract

Abstract. Voltage-gated sodium channels (VGSC) play important roles in the development and progression of many cancers. We report the possible roles of VGSC in human ovarian cancer. Relative mRNA expression levels of Nav1.1, Nav1.3, Nav1.4 and Nav1.5, analyzed by RT-PCR, were significantly higher in ovarian cancers cells compared with normal ovarian tissues; relative mRNA expression levels of Nav1.2, Nav1.4, Nav1.5 and Nav1.7 were significantly increased in highly metastatic ovarian cancer cells (Caov-3 and SKOV-3) compared with low-metastatic ovarian cancer cells (Anglne). Treatment of 30 μM tetrodotoxin reduced by 50-60% migration and invasion of Caov-3 and SKOV-3 without affecting proliferation. Real-time PCR, Western blot analysis and immunohistochemistry assays revealed that functional expression levels of Nav1.5 might be correlated with the grade and metastasis of ovarian cancer. Our findings suggested that abnormal expression of Nav1.5 could be an integral component of the metastatic process in human ovarian cancer and might serve as a therapeutic target in ovarian cancer treatment. IntroductionOvarian cancer is the most fatal cancer in women in the world. The overwhelming majority of patients are found at advanced disease stage because of no obvious symptoms. Therefore, it is necessary to find effective diagnosis and therapy methods (1).Ion channels are functionally expressed in almost all tissues and cell types as the main signaling molecules (2). With the development of patch clamp technique and molecular biology, recent studies have revealed that ion channels were associated with different aspects of carcinogenic process by involving in cell proliferation, multidrug resistance, migration and invasion (3,4). The functional expression levels of potassium, calcium and chloride channels had been widely investigated over the past few decades, but little is known about the sodium channels in ovarian cancer (5,6).Voltage-gated sodium channel (VGSC) mediates an inward sodium current during the initial phase of potential action in excitable cells, composed of principal · subunit (VGSC·) and auxiliary ß subunits (VGSCß) (7). A window of voltage has been found at cancer cellular normal membrane potential, where there is a continuous entry of sodium because of the partial opening of VGSC·, the entry sodium might be responsible for the disrupting intracellular ion homeostasis (6,8). Therefore, it is important to investigate the roles of VGSC· in carcinogenic process. The functional subunits of VGSC· are the Nav1 family (Nav1.1-1.9), each member of the Nav1 family consists of 4 homologous domains (D1-D4) and every domain has 6 transmembrane segments (S1-S6) (9). Tetrodotoxin (TTX) is the specific blocker of VGSC, according to the sensitivity to TTX, VGSC is described TTX-sensitive (TTX-S; Nav1.1-1.4, Nav1.6-1.7) and TTX-resistant (TTX-R; Nav1.5, Nav1.8-1.9) (10). Among the family, Nav1.5 and Nav1.7 have been found to potentiate metastasis of many cancers (11-13).The aim of this study was to investigate the function...

The Emerging Role of Voltage-Gated Sodium Channels in Tumor Biology

“…The relative mRNA expression levels of Nav1.1, Nav1.3, Nav1.4, and Nav1.5 in ovarian cancer cells are significantly higher than those in normal ovarian tissues (5). Furthermore, the mRNA expression levels of Nav1.2, Nav1.4, Nav1.5, and Nav1.7 are greatly increased in the strongly metastatic ovarian cancer cell lines, Caov-3 and SKOV-3, compared to the weakly metastatic Anglne cells.…”

“…Furthermore, these molecules are also present in cancer cells from e.g., colon, breast, prostate, and non-small cell lung cancer. In these transformed cells they are involved in tumor growth, invasion, and metastasis (5–9). This contribution of VGSC to cancer malignancy and to the resistance of tumors to chemotherapy drugs has become the focus of research.…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…In this regard, VGSCs play an important role in the development and progression of different cancers, since they have been correlated with different events of the carcinogenic process, including cell proliferation, migration, invasion, and Multi-Drug Resistance (MDR) [ 125 , 126 ]. NaV1.2 channel increased expression has been observed in different cancer types, including prostate [ 127 ] and ovarian cancer, where it is involved in regulating migration and invasion of highly metastatic cancer cells [ 128 ]. Interestingly, rapid estrogen actions on different ion channels’ functionality have been reported, and both endogenous and exogenous estrogens can bind NaV1.2, other VGSCs and other ion channels, to regulate their activity [ 129 , 130 ] ( Figure 2 ).…”

A mesofluidic multiplex immunosensor for detection of circulating cytokeratin-positive cells in the blood of breast cancer patients

“…The human breast cancer MCF7 cell line used herein underwent long-term passages (>70), thus gaining high expression of HER2 (Wang and Wang 2010). Cells were grown in DMEM (Dulbecco's Modified Eagle Medium, Gibco BRL) containing 10% FCS, 2 mM glutamine, 100 U/mL penicillin and 100 μg/mL streptomycin, and cultured until subconfluence.…”