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Abstract
BackgroundMetastasis accounts for the most deaths in patients with hepatocellular carcinoma (HCC). Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown.MethodsImmunohistochemistry was performed to determine the expression of RANK in HCC tissue (n = 398). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to examine the expression of RANK, E-cadherin, N-cadherin, vimentin, Snail, Slug, Twist and MMPs in HCC cells. Wound healing and Transwell assays were used to evaluate cell migration and invasion ability.ResultsWe found that expression of RANK, the receptor of RANKL, was significantly higher in HCC tumor tissues than in peritumor liver tissues (p<0.001). Constitutive expression of RANK was detected in HCC cell lines, which can be up-regulated when HCC cells were stimulated with RANKL. Notably, in vitro experiments showed that activation of RANKL-RANK axis significantly promoted migration and invasion ability of HCC cells. In addition, RANKL stimulation increased the expression levels of N-cadherin, Snail, and Twist, while decreased the expression of E-cadherin, with concomitant activation of NF-κB signaling pathway. Moreover, administration of the NF-κB inhibitor attenuated RANKL-induced migration, invasion and epithelial-mesenchymal transition of HCC cells.ConclusionsRANKL could potentiate migration and invasion ability of RANK-positive HCC cells through NF-κB pathway-mediated epithelial-mesenchymal transition, which means that RANKL-RANK axis could be a potential target for HCC therapy.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of death by cancer, with more than half a million new cases worldwide each year [1,2]
The results showed that RANK was obviously overexpressed in tumor tissues compared to the peritumor tissues in hepatocellular carcinoma (HCC)
Stainingintensity analysis demonstrated that percentage of HCC samples falling into grades 2, + was significantly lower in tumor tissues (15.33% & 50.50%) than in peritumor tissues (26.13% & 60.30%), whereas percentage of samples falling into grades ++, +++ was significantly higher in tumor tissues (16.33% &17.84%) than in peritumor tissues (11.56% &2.01%) (p,0.001; Figure 1A), which means a higher level of activated RANKL-RANK signaling pathway in tumor tissues than that in peritumor tissues
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of death by cancer, with more than half a million new cases worldwide each year [1,2]. The induction of EMT can be triggered by transcription factors such as Snail, Slug, and Twist, which simultaneously repress the expression of genes that are required for the epithelial phenotype and induce the expression of genes required for mesenchymal properties [10]. The expression of these transcription factors is modulated by a number of signaling molecules, including nuclear factor kappa B (NF-kB) [10,11]. Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown
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