Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy.
Centre for Applied Biomedical Research - CRBA, University of Bologna, Policlinico di Sant'Orsola, 40138, Bologna, Italy.
J Exp Clin Cancer Res. 2023 Jun 10;42(1):145. doi: 10.1186/s13046-023-02718-w.
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.
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.
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.
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.
代谢重编程是癌症的一个众所周知的标志物，它代表了肝细胞癌（HCC）发展过程中的早期事件。最近批准的几种分子靶向药物已经彻底改变了晚期 HCC 患者的治疗方法。然而，缺乏循环生物标志物仍然影响着患者的分层，以进行针对性治疗。在这种情况下，迫切需要生物标志物来辅助治疗选择，并需要新的、更有效的治疗组合来避免耐药表型的发展。本研究旨在证明 miR-494 参与 HCC 的代谢重编程，确定新的 miRNA 治疗组合，并评估 miR-494 作为循环生物标志物的潜力。
生物信息学分析确定了 miR-494 的代谢靶标。对 HCC 患者和临床前模型中的葡萄糖 6-磷酸酶催化亚基（G6pc）进行 QPCR 分析。功能分析和代谢测定评估了 G6pc 靶向和 miR-494 在 HCC 细胞代谢变化、线粒体功能障碍和 ROS 产生中的作用。活细胞成像分析评估了 miR-494/G6pc 轴在应激条件下 HCC 细胞生长中的作用。检测索拉非尼治疗的 HCC 患者和 DEN-HCC 大鼠的循环 miR-494 水平。
miR-494 通过靶向 G6pc 和 HIF-1A 通路激活诱导 HCC 细胞的代谢向糖酵解表型转变。miR-494/G6pc 轴在癌细胞的代谢可塑性中发挥积极作用，导致糖原和脂滴积累，有利于细胞在恶劣环境条件下的存活。在临床前模型和 HCC 患者的初步队列中，高血清 miR-494 水平与索拉非尼耐药相关。在 HCC 细胞中，抗 miR-494 与索拉非尼或 2-脱氧葡萄糖联合治疗观察到增强的抗癌效果。
miR-494/G6pc 轴对于癌细胞的代谢重编程至关重要，并与不良预后相关。miR-494 值得作为索拉非尼反应可能性的候选生物标志物进行进一步研究。miR-494 代表了与索拉非尼或代谢干扰分子联合治疗不适宜免疫治疗的 HCC 患者的有前途的治疗靶点。
