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.

Knowledge mapping of MIRNA in hepatocellular carcinoma from 2012-2022:a bibliometric analysis

“…However, Sorafenib has also been associated with widespread resistance and side effects in clinical practice [35][36] . Available evidence suggests that miRNAs are involved in multiple aspects of tumor cell differentiation, proliferation, regulation, invasion, metastasis, autophagy, and tumor microenvironment [37][38][39] , and can reverse Sorafenib resistance in HCC treatment [40][41][42] and enhance the clinical e cacy of Sorafenib. Although hepatocellular carcinoma treatment has come to the era of immunotherapy in recent years, especially since the FDA has approved the combination of atelelizumab and bevacizumab for improving overall survival in patients with advanced HCC [43][44] , Sorafenib is still considered as the rst-line agent for systemic treatment of HCC.…”

Prognostic value of high FOXO3a expression in patients with solid tumors: A meta-analysis and systematic review

“…Post-translational modifications of FOXO3a can regulate its transcriptional activity and nuclear location, enabling it as a potential target for novel strategy in cancer treatment. 42,43 Some studies reported that high expression of FOXO3a was associated with improved OS in patients with solid tumor. However, other studies indicated that the high expression of FOXO3a was related to poor OS in comparable patients.…”

Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis

“…The mice were euthanized after 21 days of inoculation, and the s.c. tumor were dissected and analyzed. Sorafenib significantly inhibited HCC growth, [26] but the ABX treatment group significantly reduced its effect. However, after resupplementation with NaBu in the ABX treatment group, the tumor volume was significantly reduced post targeted therapy (Figure 5L, M).…”