Abstract
The existence of cancer stem cells (CSCs) is central to the pathogenesis and therapeutic target of human hepatocellular carcinoma. The aim of this study was to investigate the effects of casticin on epithelial-mesenchymal transition (EMT) of liver cancer stem cells (LCSCs) derived from the SMMC-7721 cell line. Our results demonstrated that CD133+ sphere-forming cells (SFCs) sorted from the SMMC-7721 cell line not only possessed a higher capacity to form tumor spheroids in vitro, but also had a greater potential to form tumors when implanted in Balb/c-nu mice, indicating that CD133+ SFCs possessed similar traits to LCSCs. Casticin increased the expression levels of E-cadherin and decreased those of N-cadherin in LCSCs. Treatment of LCSCs with casticin for 48 h also decreased the levels of the EMT-associated transcription factor, Twist. Overexpression of Twist attenuated the casticin-induced regulation of E-cadherin and N-cadherin protein expression, as well as the EMT capacity of LCSCs. In conclusion, CD133+ SFCs of the SMMC-7721 cell line may represent a subpopulation of LCSCs with the characteristics of EMT. Furthermore, casticin targeted LCSCs through the inhibition of EMT by downregulating Twist.
Highlights
Hepatocellular carcinoma (HCC) is the third most common lethal malignancy and the fifth most common type of cancer worldwide
We aimed to investigate the effects of casticin on the epithelial‐mesenchymal transition (EMT) of liver cancer stem cells (LCSCs) derived from the SMMC‐7721 cell line
sphere‐forming cells (SFCs) expressed a higher N-cadherin protein levels, which was typically associated with mesenchymal cells, and a lower expression of epithelium-associated E-cadherin protein. (C) Treatment of casticin resulted in downregulation of N-cadherin and the upregulation of E-cadherin in CD133+ SFCs of the SMMC
Summary
Hepatocellular carcinoma (HCC) is the third most common lethal malignancy and the fifth most common type of cancer worldwide. In 2008, there were an estimated 748,300 new liver cancer cases and 695,900 cancer mortalities worldwide [1,2]. Half of these cancer cases and cancer‐associated mortalities were estimated to occur in China [3]. Liver transplantation or surgical resection remain the first‐line treatments for HCC [4]. Patients often present symptoms at the advanced stages of HCC and, the first‐line treatments are not effective for the majority of HCC cases. For patients with HCC at the advanced stages, chemotherapy via either transarterial chemoembolization or a systemic route is the second‐line treatment. The efficacy of the regimens is limited due to the highly chemoresistant nature of the tumor and the toxicity of traditional chemotherapy [5,6,7]
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