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

Guo, Feifei; Estévez-Vázquez, Olga; Benedé-Ubieto, Raquel; Maya-Miles, Douglas; Zheng, Kang; Gallego-Durán, Rocío; Rojas, Ángela; Ampuero, Javier; Romero-Gómez, Manuel; Philip, Kaye; Egbuniwe, Isioma U.; Chen, Chaobo; Simon, Jorge; Delgado, Teresa C.; Martínez-Chantar, María Luz; Sun, Jie; Reissing, Johanna; Bruns, Tony; Lamas-Paz, Arantza; Moral, Manuel Gómez del; Woitok, Marius Maximilian; Vaquero, Javier; Regueiro, José R.; Liedtke, Christian; Trautwein, Christian; Bañares, Rafael; Cubero, Francisco Javier; Nevzorova, Yulia A.

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.

Citation

Guo, F., Estévez-Vázquez, O., Benedé-Ubieto, R., Maya-Miles, D., Zheng, K., Gallego-Durán, R., …Nevzorova, Y. A. (2022). 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), Article 192. https://doi.org/10.3390/cancers14010192

• Journal Article Type: Article
• Acceptance Date: Dec 20, 2021
• Online Publication Date: Dec 31, 2021
• Publication Date: Jan 1, 2022
• Deposit Date: Jan 13, 2022
• Publicly Available Date: Jan 13, 2022
• Journal: Cancers
• Electronic ISSN: 2072-6694
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 14
• Issue: 1
• Article Number: 192
• DOI: https://doi.org/10.3390/cancers14010192
• Keywords: Cancer Research; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/7225714
• Publisher URL: https://www.mdpi.com/2072-6694/14/1/192