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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. [ABSTRACT FROM AUTHOR]

Chemo-resistance to conventional therapy is a major barrier requiring further investigation in hepatocellular carcinoma (HCC). Cancer stem like cells (CSCs) contribute to the tumorigenicity, progression, and chemo-resistance of malignancies. Studies have implicated the anti-cancer effects of arsenic trioxide (ATO) and have explored the underlying mechanisms. However, whether ATO might reverse chemo-resistance by inhibiting the CSC like properties remains under investigation. Here, we explored the potential of ATO in chemotherapy in constructed multiple drug resistant (MDR) liver cancer cells. ATO re-sensitized the MDR Bel-7402 cells (BelMDR) cells to chemotherapeutic drugs, an effect mediated by the inhibition of NF-κB pathway and CSCs properties. For the molecular mechanisms, via inducing the DNA de-methylation, ATO activated the microRNA-148a (miR-148a), leading to the repression of NF-κB pathway by targeting the 3′-UTR of p65. In summary, epigenetic regulation of miR-148a by ATO is an important mechanism in drug resistance that decreases the expression of NF-κB and hence represses CSC like phenotype. These findings may suggest a novel mechanism for HCC treatment. • ATO enhances sensitivity to chemotherapy in MDR liver cancer cells. • NF-κB is involved in ATO- reversal of CSC-like phenotypes and MDR. • ATO represses NF-κB through the demethylation of miR-148a in HCCMDR cells. • ATO reversal of CSC-like phenotypes is partially dependent on miR-148a. • ATO reversal of MDR is triggered by miR-148a inhibition. [ABSTRACT FROM AUTHOR]