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

Journal of Experimental & Clinical Cancer Research

Research

Giuseppe Galvani¹  Francesca Fornari¹  Elisa Monti¹  Ilaria Leoni¹  Catia Giovannini²  Claudio Stefanelli³  Camelia Alexandra Coada⁴  Fabio Piscaglia⁵  Matteo Cescon⁶  Matteo Ravaioli⁶  Manuela Ferracin⁷  Massimo Negrini⁸  Francesco Vasuri⁹  Romana Fato^1,10  Irene Liparulo^1,10  Nicola Rizzardi^1,10  Francesca Valenti^1,10  Mattia Melli^1,10  Christian Bergamini^1,10  Laura Gramantieri^1,11 

[1] Centre for Applied Biomedical Research - CRBA, University of Bologna, Policlinico di Sant’Orsola, 40138, Bologna, Italy;Department for Life Quality Studies, University of Bologna, 47921, Rimini, Italy;Centre for Applied Biomedical Research - CRBA, University of Bologna, Policlinico di Sant’Orsola, 40138, Bologna, Italy;Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy;Department for Life Quality Studies, University of Bologna, 47921, Rimini, Italy;Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy;Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy;Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti, 9, 40138, Bologna, Italy;Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy;Hepato-biliary Surgery and Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy;Department of Medical and Surgical Sciences, University of Bologna, 40138, Bologna, Italy;IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy;Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44100, Ferrara, Italy;Department of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy;Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy;Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti, 9, 40138, Bologna, Italy;

关键词: HCC;    microRNA;    miR-494;    G6pc;    Metabolism;    Biomarker;    Sorafenib;   

DOI  :  10.1186/s13046-023-02718-w

 received in 2023-02-17, accepted in 2023-05-22,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMetabolic 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.MethodsBioinformatics 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.ResultsMiR-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.ConclusionsMiR-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.

【 授权许可】

CC BY   
© The Author(s) 2023

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