MiR-494 induces metabolic changes through G6pc targeting and modulates sorafenib response in hepatocellular carcinoma

Abstract

Background Metabolic reprogramming is a well-known marker of cancer, and it represents an early event during hepatocellular carcinoma (HCC) development. The recent approval of several molecular targeted agents has revolutionized the management of advanced HCC patients. Nevertheless, the lack of circulating biomarkers still affects patient stratification to tailored treatments. In this context, there is an urgent need for biomarkers to aid treatment choice and for novel and more effective therapeutic combinations to avoid the development of drug-resistant phenotypes. This study aims to prove the involvement of miR-494 in metabolic reprogramming of HCC, to identify novel miRNA-based therapeutic combinations and to evaluate miR-494 potential as a circulating biomarker. Methods Bioinformatics analysis identified miR-494 metabolic targets. QPCR analysis of glucose 6-phosphatase catalytic subunit (G6pc) was performed in HCC patients and preclinical models. Functional analysis and metabolic assays assessed G6pc targeting and miR-494 involvement in metabolic changes, mitochondrial dysfunction, and ROS production in HCC cells. Live-imaging analysis evaluated the effects of miR-494/G6pc axis in cell growth of HCC cells under stressful conditions. Circulating miR-494 levels were assayed in sorafenib-treated HCC patients and DEN-HCC rats. Results MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions. High miR-494 serum levels associated with sorafenib resistance in preclinical models and in a preliminary cohort of HCC patients. An enhanced anticancer effect was observed for treatment combinations between antagomiR-494 and sorafenib or 2-deoxy-glucose in HCC cells. Conclusions MiR-494/G6pc axis is critical for the metabolic rewiring of cancer cells and associates with poor prognosis. MiR-494 deserves attention as a candidate biomarker of likelihood of response to sorafenib to be tested in future validation studies. MiR-494 represents a promising therapeutic target for combination strategies with sorafenib or metabolic interference molecules for the treatment of HCC patients who are ineligible for immunotherapy.

Noncoding RNAs in Hepatocellular Carcinoma: Potential Applications in Combined Therapeutic Strategies and Promising Candidates of Treatment Response

“…Since two miR-10b inhibitors have been developed based on advances in nanotechnology (TTX-MC138 and RGLS5579), demonstrating an effective anticancer activity in preclinical models [50], this miRNA investigation holds promise both as a therapeutic target and a predictive biomarker. Finally, a study by our research group reported the association between high miR-494 serum levels and sorafenib resistance in HCC patients at baseline [68]. In addition, we underlined the relationship between miR-494 serum levels and genes involved in the metabolic reprogramming of cancer cells, pointing out the possibility that circulating levels of this miRNA might not only predict sorafenib response but also identify tumors with a deregulated metabolism that could benefit from combined TKI and antagomiR or metabolic interference strategies.…”

“…We demonstrated that the miR-494/G6pc axis contributes to the metabolic plasticity of cancer cells, favoring the accumulation of glycogen and lipid droplets that are exploited in the case of critical metabolic conditions (e.g., glucose deprivation), giving an advantage to the uncontrolled proliferation of malignant cells. We also showed that the miR-494/G6pc axis promotes sorafenib resistance and proposed combining antagomiR-based treatments with sorafenib or 2-deoxyglucose (2-DG) for HCC patients who may develop sorafenib resistance and who are ineligible for immunotherapy [68]. An interesting study by Zhang et al [69] demonstrated the pivotal role of the miR-30a-5p/CLCF1 axis in modulating the metabolic shift toward the aerobic glycolysis of SR HepG2 cells and xenograft tumors.…”

JAK1 Is a Novel Target of Tumor- and Invasion-Suppressive microRNA 494-5p in Colorectal Cancer

“…Towards this end, it has already been shown that miR-494 could play a critical role during imatinib treatment in resistant prostate cancer and CML leukemic stem cells [ 85 , 86 ]. Additionally, high expression of miR-494 was shown to be associated with the induction of sorafinib resistance in hepatocellular carcinoma [ 87 , 88 , 89 ]. Another study aiming to explore the ability of miR-494 and FGFR2 to regulate the cancer-initiating cell phenotype and the therapeutic efficacy of lapatinib in HER2-positive gastric cancer found that increased miR-494 expression was able to reduce lapatinib resistance in these cells [ 90 ].…”

The roles and molecular mechanisms of non-coding RNA in cancer metabolic reprogramming

“…However, the main way to acquire energy in cancer cells is aerobic glycolysis even under the condition of adequate oxygen. Accumulated evidence suggests there are numerous glucose metabolism-associated ncRNAs dysregulated in cancers resulting in mitochondrial dysfunction, abundant activation of key enzymes, altered isozyme profiles and dysregulated glucose metabolic signalling pathways [ 64 – 66 ]. Current progress in the role of ncRNAs in glucose metabolism has been summarized in Fig.…”