A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy

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Guo, Feifei and Estevez Vázquez, Olga and Benedé Ubieto, Raquel and Maya Mile, Douglas and Zheng, Kang and Gallego Durán, Rocío and Rojas Ávalos, Ángela and Ampuero, Javier and Romero Gómez, Manuel and Philip, Kaye and Egbuniwe, Isioma U. and Chen, Chaobo and Simon, Jorge and Delgado, Teresa C. and Martínez Chantar, Maria L. and Sun, Jie and Reissing, Johanna and Bruns, Tony and Lamas Paz, Arantza and Gómez del Moral Martín-Consuegra, Manuel María and Woitok, Marius Maximilian and Vaquero Martín, Javier and Regueiro, José R. and Liedtke, Christian and Trautwein, Christian and Bañares Cañizares, Rafael and Cubero Palero, Francisco Javier and Nevzorova, Yulia A. (2021) A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy. Cancers, 14 (1). pp. 1-19. ISSN 2072-6694

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Official URL: https://doi.org/10.3390/cancers14010192



Abstract

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.


Item Type:Article
Uncontrolled Keywords:metabolic-associated fatty liver disease (MAFLD); c-myc; oncogene; tumorigenesis; metformin
Subjects:Medical sciences > Medicine > Gastroenterology and Hepatology
Medical sciences > Medicine > Oncology
ID Code:74303
Deposited On:02 Sep 2022 15:37
Last Modified:05 Sep 2022 07:10

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