ABSTRACT
Cancer initiating cells (CICs) are responsible for the unrestrained cell growth and chemoresistance of malignant tumors. Histone demethylation has been shown to be crucial for self-renewal/differentiation of stem cells, but it remains elusive whether lysine-specific demethylase 1 (LSD1) regulates the stemness properties of CICs. Here we report that the abundant expression of leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is associated with the progression of hepatocellular carcinoma (HCC). Lgr5(+) HCC cells behave similarly to CICs and are highly tumorigenic and resistant to chemotherapeutic agents. Importantly, Lgr5(+) cells express higher levels of LSD1, which in turn regulates Lgr5 expression and promotes the self-renewal and drug resistance of Lgr5(+) CICs. Mechanistically, LSD1 promotes ß-catenin activation by inhibiting the expression of several suppressors of ß-catenin signaling, especially Prickle1 and APC in Lgr5(+) CICs, by directly regulating the levels of mono- and di-methylation of histone H3 lysine-4 at the promoters of these genes. Furthermore, LSD1-associated activation of the ß-catenin signaling is essential for maintaining the activity of Lgr5(+) CICs. Together, our findings unravel the LSD1/Prickle1/APC/ß-catenin signaling axis as a novel molecular circuit regulating the stemness and chemoresistance of hepatic Lgr5(+) CICs and provide potential targets to improve chemotherapeutic efficacies against HCC.
Subject(s)
Carcinoma, Hepatocellular/pathology , Drug Resistance, Neoplasm/genetics , Histone Demethylases/physiology , Liver Neoplasms/pathology , Neoplastic Stem Cells/pathology , beta Catenin/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Down-Regulation , Gene Expression Regulation, Neoplastic , Histone Demethylases/genetics , Humans , Liver Neoplasms/genetics , Male , Mice , Mice, Nude , Neoplastic Stem Cells/metabolism , Receptors, G-Protein-Coupled/metabolism , Tumor Cells, Cultured , Wnt Signaling Pathway/geneticsABSTRACT
To know the research progress of cupping therapy all over the world, the authors analyze the research of cupping therapy in recent 5 years. It indicates that cupping therapy can be applied to extensive curable disease, but has poor clinical evidence. Some improvements in the mechanism research of cupping therapy have been made, but it needs further research. The adverse events of cupping therapy attract attention. The standardization of cupping therapy has emerged.
