Cetrimonium Bromide Inhibits Cell Migration and Invasion of Human Hepatic SK-HEP-1 Cells Through Modulating the Canonical and Non-canonical TGF-β Signaling Pathways

Abstract

Background/Aim: Cetrimonium bromide (CTAB), a quaternary ammonium surfactant, is an antiseptic agent against bacteria and fungi. However, the mechanisms by which its pharmacological actions affect epithelialmesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as adenocarcinoma in SK-HEP-1 cells, have not been investigated. We, thereby, investigated whether CTAB inhibits cellular mobility and invasiveness of human hepatic adenocarcinoma in SK-HEP-1 cells. Materials and Methods: SK-HEP-1 cells were treated with CTAB, and subsequent migration and invasion were measured by wound healing and transwell assays. Protein expression was detected by immunoblotting analysis. Results: Our data revealed that treatment of SK-HEP-1 cells with CTAB altered their mesenchymal spindle-like morphology. CTAB exerted inhibitory effects on the migration and invasion of SK-HEP-1 cells dose-dependently, and reduced protein levels of matrix metalloproteinase-2 (MMP-2), snail, slug, twist, vimentin, fibronectin, Smad2, Smad3, Smad4, kinase (PI3K), p-PI3K, Akt, p-Akt, βcatenin, mammalian target of rapamycin (mTOR), p-mTOR, p-p70S6K, p-extracellular signal-regulated kinases (ERK)1/2, p-p38 mitogen-activated protein kinase (MAPK) and p-c-Jun N-terminal kinase (JNK), but increased protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), TIMP-2, claudin-1 and p-GSK3β. Based on these observations, we suggest that CTAB not only inhibits the canonical transforming growth factor-β (TGF-β) signaling pathway though reducing SMADs (an acronym from the fusion of Caenorhabditis elegans Sma genes and the Drosophila Mad, Mothers against decapentaplegic proteins), but also restrains the non-canonical TGF-β signaling including MAPK pathways like ERK1/2, p38 MAPK, JNK and PI3K. Conclusion: CTAB is involved in the suppression of TGF-βmediated mesenchymal phenotype and could be a potent medical agent for use in controlling the migration and invasion of hepatic adenocarcinoma.Liver cancer, also known as hepatic cancer, accounts for more than 4.7 percent of all cancer cases and was ranked as the third highest mortality cause among the world's most common cancers in 2018 (8.2%) (1). Liver contain parenchymal and non-parenchymal cells (NPCs) (2). Hepatocytes are the major parenchymal cells and constitute about 80% of the liver population. Parenchymal liver cancer can be classified into two major types: i) hepatocellular carcinoma (HCC) and ii) hepatoblastoma. Non-parenchymal 3621 *These Authors contributed equally to this study.

MicroRNA Expression Profiling Involved in Borax-Induced Anti-Tumor Effect Using Gene-Chip Analysis

“…Furthermore, KEGG pathway enrichment analysis showed that the target genes of differentially expressed miRNAs in HepG2 cells following borax treatment for 2 h mainly participated in the MAPK, TGF-β, NF-κB and cAMP signaling pathways. The MAPK signaling pathway is generally involved in cell proliferation, apoptosis and differentiation [31]; TGF-β signaling is often activated and not attenuated during HCC progression; thus, TGF-β may be a therapeutic target for the treatment of liver cancer [32]. NF-κB is a ubiquitous transcription factor in mammals that enters the cell nucleus and enhances gene expression by binding to the κB site within the promoter.…”

The inhibitory effect of CTAB on human osteosarcoma through the PI3K/AKT signaling pathway

“…In addition, CTAB has been used as an effective cytotoxic lavage solution in breast cancer surgery (25). CTAB may also suppress the invasion and metastasis of hepatocellular carcinoma cells by inhibiting TGF signal transduction (26). As bone metastasis is closely related to poor prognosis, controlling the invasion and metastasis of osteosarcoma cells is one of the difficulties in the treatment of osteosarcoma (22,27).…”

MicroRNA expression profiling involved in Borax-induced anti-tumor effect using gene-chip analysis

“…To precision select the target genes affected by miRNAs, GO enrichment analyses showed that the processes significantly altered by borax involved biological regulation, cell junction, metabolism, and protein binding. Furthermore, KEGG pathway enrichment analysis showed that the target genes of differentially expressed miRNAs in HepG2 cells following borax treatment for 2 h major participated in MAPK signaling pathway, TGF-beta signaling pathway, NF-kappa B signaling pathway, cAMP signaling pathway, etc; MAPK signaling pathway, a mitogen-activated protein kinase pathway, which is generally involved in cell proliferation, apoptosis and differentiation [31]; TGF-β signaling (TGF-beta signaling) is often activated and not attenuated during the malignancy of hepatocellular carcinoma cells, so TGF-β could be a therapeutic target for the treatment of liver cancer [32]. NF-kappa B, an ubiquitous transcription factor in mammals, which enters into cellular nucleus and enhances gene expression by binding to κB site within promoter.…”