Inhibition of the cancer stem cells-like properties by arsenic trioxide, involved in the attenuation of endogenous transforming growth factor beta signal

• Published in: Toxicological sciences 2015-01, Vol.143 (1), p.156-164
• Main Authors: Li, Yuan, Jiang, Fei, Liu, Qinqiang, Shen, Jian, Wang, Xingxing, Li, Zhong, Zhang, Jianping, Lu, Xiang
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; AC133 Antigen; Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antineoplastic Agents - pharmacology; Arsenicals - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - mortality; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Glycoproteins - genetics; Glycoproteins - metabolism; Humans; Kaplan-Meier Estimate; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - mortality; Liver Neoplasms - pathology; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oxides - pharmacology; Peptides - genetics; Peptides - metabolism; RNA Interference; Signal Transduction - drug effects; Smad3 Protein - genetics; Smad3 Protein - metabolism; Time Factors; Transfection; Transforming Growth Factor beta - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfu218

The elevation of cancer stem cells (CSCs)-like properties is involved in the initiation and progression of various human cancers. Current standard practices for treatment of cancers are less than satisfactory because of CSCs-mediated recurrence. For this reason, targeting the CSCs or the cancer cells with CSCs-like properties has become the new approach for the cancer treatments. In addition to treating leukemia, arsenic trioxide (As₂O₃) also suppresses other solid tumors. However, the roles of As₂O₃ in the regulation of CSCs-like properties remain largely uninvestigated. Here by using sphere formation assay, luciferase reporter assay, and some other molecular biology approaches, we found that As₂O₃ attenuated the CSCs-like properties in human hepatocellular carcinoma (HCC). Briefly, in HCC cells and mice xenograft models, As₂O₃ improved the expression of miR-491 by DNA-demethylation. MiR-491, which targeted the SMAD3-3'-UTR, decreased the expressions of SMAD3, and inhibited the CSCs-like properties in HCC cells. Knockdown of either miR-491 or SMAD3 attenuated the As₂O₃-induced inhibition of endogenous transforming growth factor beta signal and the CSCs-like properties. Further, in HCC patients, miR-491 is inversely correlated with the expressions of SMAD3, CD133, and the metastasis/recurrence outcome. By understanding a novel mechanism whereby As₂O₃ inhibits the CSCs-like properties in HCC, our study would help in the design of future strategies of developing As₂O₃ as a potential HCC chemopreventive agent when used alone or in combination with other current drugs.