De-methylation of miR-148a by arsenic trioxide enhances sensitivity to chemotherapy via inhibiting the NF-κB pathway and CSC like properties.

Abstract

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.

• Authors: Yuting Wang, Fei Jiang, Kailin Jiao, Liang Ju, Qinqiang Liu, Yuan Li, Lin Miao, Zhong Li
• Journal: Experimental cell research (Exp Cell Res) Vol. 386 Issue 2 Pg. 111739 (01 15 2020) ISSN: 1090-2422 [Electronic] United States
• PMID: 31759055 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 3' Untranslated Regions
• Antineoplastic Agents
• MIRN148 microRNA, human
• MicroRNAs
• Transcription Factor RelA
• Oxaliplatin
• Arsenic Trioxide
• Fluorouracil

Topics

• 3' Untranslated Regions
• Antineoplastic Agents (pharmacology)
• Arsenic Trioxide (pharmacology)
• Cell Line, Tumor
• DNA Methylation (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epigenesis, Genetic
• Fluorouracil (pharmacology)
• Gene Expression Regulation, Neoplastic
• Hepatocytes (drug effects, metabolism, pathology)
• Humans
• MicroRNAs (genetics, metabolism)
• Neoplastic Stem Cells
• Oxaliplatin (pharmacology)
• Signal Transduction
• Transcription Factor RelA (genetics, metabolism)