%0 Journal Article
%A Guo, Feifei
%A Estevez Vázquez, Olga
%A Benedé Ubieto, Raquel
%A Maya Mile, Douglas
%A Zheng, Kang
%A Gallego Durán, Rocío
%A Rojas Ávalos, Ángela
%A Ampuero, Javier
%A Romero Gómez, Manuel
%A Philip, Kaye
%A Egbuniwe, Isioma U.
%A Chen, Chaobo
%A Simon, Jorge
%A Delgado, Teresa C.
%A Martínez Chantar, Maria L.
%A Sun, Jie
%A Reissing, Johanna
%A Bruns, Tony
%A Lamas Paz, Arantza
%A Woitok, Marius Maximilian
%A Regueiro, José R.
%A Liedtke, Christian
%A Trautwein, Christian
%A Bañares Cañizares, Rafael
%A Cubero Palero, Francisco Javier
%A Benede Ubieto, Raquel
%A Gómez Del Moral Martín-Consuegra, Manuel María
%A Vaquero Martín, Francisco Javier
%A Nevzorova, Yulia
%T A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy
%D 2021
%@ 2072-6694
%U https://hdl.handle.net/20.500.14352/71932
%X Background: Metabolic-associated fatty liver disease (MAFLD) has risen as one of the leading etiologies for hepatocellular carcinoma (HCC). Oncogenes have been suggested to be responsible for the high risk of MAFLD-related HCC. We analyzed the impact of the proto-oncogene c-MYC in the development of human and murine MAFLD and MAFLD-associated HCC. Methods: alb-myctg mice were studied at baseline conditions and after administration of Western diet (WD) in comparison to WT littermates. c-MYC expression was analyzed in biopsies of patients with MAFLD and MAFLD-associated HCC by immunohistochemistry. Results: Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old alb-myctg mice. Middle-aged alb-myctg exhibited liver steatosis and increased triglyceride content. Liver injury and inflammation were associated with elevated ALT, an upregulation of ER-stress response and increased ROS production, collagen deposition and compensatory proliferation. At 52 weeks, 20% of transgenic mice developed HCC. WD feeding exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and tumor prevalence. Therapeutic use of metformin partly attenuated the spontaneous MAFLD phenotype of alb-myctg mice. Importantly, upregulation and nuclear localization of c-MYC were characteristic of patients with MAFLD and MAFLD-related HCC. Conclusions: A novel function of c-MYC in MAFLD progression was identified opening new avenues for preventative strategies.
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