MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1.

Abstract

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the sensitivity of HCC to sorafenib. We demonstrated that miR-124-3p.1 downregulation is associated with early recurrence in HCC patients who underwent curative surgery and sorafenib resistance in HCC cell lines. Regarding the mechanism of this phenomenon, we identified FOXO3a, an important cellular stress transcriptional factor, as the key factor in the function of miR-124-3p.1 in HCC. We showed that miR-124-3p.1 binds directly to AKT2 and SIRT1 to reduce the levels of these proteins. Furthermore, we showed that AKT2 and SIRT1 phosphorylate and deacetylate FOXO3a. We also found that miR-124-3p.1 maintains the dephosphorylation and acetylation of FOXO3a, leading to the nuclear location of FOXO3a and enhanced sorafenib-induced apoptosis. Moreover, the combination of miR-124-3p.1 mimics and sorafenib significantly enhanced the curative efficacy of sorafenib in a nude mouse HCC xenograft model. Collectively, our data reveal that miR-124-3p.1 represents a predictive indicator of early recurrence and sorafenib sensitivity in HCC. Furthermore, we demonstrate that miR-124-3p.1 enhances the curative efficacy of sorafenib through dual effects on FOXO3a. Thus, the miR-124-3p.1-FOXO3a axis is implicated as a potential target for the diagnosis and treatment of HCC.

• Authors: Zhe-Bin Dong, Heng-Miao Wu, Yi-Cheng He, Zhong-Ting Huang, Yi-Hui Weng, Hong Li, Chao Liang, Wei-Ming Yu, Wei Chen
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 1 Pg. 35 (01 10 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35013144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Biomarkers, Tumor
• FOXO3 protein, human
• Forkhead Box Protein O3
• MIRN124 microRNA, human
• MicroRNAs
• Sorafenib
• AKT2 protein, human
• Proto-Oncogene Proteins c-akt
• SIRT1 protein, human
• Sirtuin 1

Topics

• Acetylation
• Animals
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Forkhead Box Protein O3 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Mice
• MicroRNAs (administration & dosage, genetics, metabolism, pharmacology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Sirtuin 1 (genetics, metabolism)
• Sorafenib (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays