ClC is not only a
ClC-3 is not only a chloride ion channel but also a regulatory protein involved in the regulation of multiple signaling pathways. The PI3K/AKT/mTOR signaling pathway plays a crucial role in regulating cell growth, migration, invasion, and distant metastasis [13,14]. Although abnormal PI3K/AKT/mTOR activation often occurs in both benign and malignant sicknesses, the mechanism of cervical cancer development modulated by the PI3K/AKT/mTOR signaling pathway remains unclear. Previous studies indicated that inhibition of PI3K/Akt/mTOR signaling pathway activation suppresses cancer cell growth, migration and invasion and inhibit cancer progression [, , ]. Moreover, studies have demonstrated that the PI3K/Akt/mTOR pathway is often dysregulated in cervical carcinoma and may be a latent therapeutic target for this malignant tumour , and suppression the PI3K/Akt/mTOR cascade can significantly attenuate cervical cancer cell proliferation and invasion . Moreover, studies indicated that ClC-3 is involved in modulating the PI3K/AKT/mTOR signaling pathway. Fujimoto et al.  found that intracellular Cl− regulation by ANO1/ClC-3 is involved in the transcription of human epidermal growth factor receptor 2 (HER2) and mediates the PI3K/AKT/mTOR signaling pathway in breast carcinoma cells. In our research, we found that inhibiting ClC-3 expression significantly decreased the expression of a phosphorylated PI3K/AKT/mTOR signaling pathway. Moreover, inhibiting the PI3K/AKT/mTOR pathway could partially suppress cervical squamous carcinoma cell migration and invasion. These results indicated that the canonical PI3K/AKT/mTOR signaling pathway participates in ClC-3-induced cervical squamous carcinoma cell migration and invasion.
Tumour NS 11394 undergoing invasion and distant metastasis required degradation of the extracellular matrix. Interestingly, in our study, ClC-3 expression is closely related to MMP-9 expression. Up-regulation of ClC-3 expression is correlated with cervical squamous carcinoma cell migration and invasion probably due to increased MMP-9 expression through the activated PI3K/AKT/mTOR signaling pathway. MMP-9 is a member of matrix metalloproteinase (MMP) family proteins, which degrade the extracellular matrix and play a vital role in migration and invasion of malignant tumours. In vitro studies demonstrate that silencing ClC-3 with SiClC-3 significantly reduces MMP-9 expression and decreases ovarian cancer cell  and glioma cell invasion and migration , but the underlying mechanism remains unclear. Fujimoto et al.  revealed that ClC-3 participates in the regulation of intracellular Cl− and HER2-positive breast carcinoma cell transcription through the PI3K/AKT/mTOR signaling pathway. Furthermore, the activated PI3K/Akt/mTOR signaling pathway significant up-regulates the expression of MMP-9 , and mTOR is an activator of MMP-9 [21,22]. mTOR is the upstream regulator of hypoxia-inducible factor (HIF)-1 alpha . HIF-1 alpha is a transcriptional factor which can active many genes including vascular endothelial growth factor (VEGF) and MMP-9 .
Conflict of interest statement
Introduction Cardiovascular diseases (CVDs) are the leading cause of death in the world. Data from WHO showed that an estimated 17.5 million people died from CVDs in 2012. Cardiac hypertrophy, primarily characterized by increased cardiomyocyte size, is considered as a major risk factor that promotes many CVDs, such as hypertension, arrhythmia, dilated cardiomyopathy, myocardial ischemia and myocardial infarction (Accornero et al., 2011, Aggarwal et al., 2014, Ai et al., 2010). Therefore, further understanding of cardiac hypertrophy underlying mechanisms may contribute to improve the prevention or treatments of CVDs. Although the mechanisms of cardiac hypertrophy are complicated, β-adrenergic receptors are thought as an important part of sympathetic activation which is tightly associated with heart function (Fu et al., 2012). Isoprenaline, an agonist of β-adrenergic receptor, could mimics sustained adrenergic stimulation and develop maladaptive cardiac hypertrophy, accompanied by reactivation of Atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC) (Chen et al., 2012, Mansier et al., 1993, Odashiro et al., 2002, Szabo et al., 1975). ANF and β-MHC are fetal cardiac genes, and their expression levels are down-regulated after birth. However, strongly increased expression levels of the cardiac ANF and β-MHC have been detected during hypertrophy and heart failure (Hong et al., 2017). ANF and β-MHC are considered to be marker genes for cardiac hypertrophy (Palazzesi et al., 2006, Saadane et al., 1999).