Inhibition of the Cancer Stem Cells-Like Properties by Arsenic Trioxide, Involved in the Attenuation of Endogenous Transforming Growth Factor Beta Signal
Open Access
- 10 October 2014
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 143 (1), 156-164
- https://doi.org/10.1093/toxsci/kfu218
Abstract
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.Keywords
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