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

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.

• Authors: Feifei Guo, Olga Estévez-Vázquez, Raquel Benedé-Ubieto, Douglas Maya-Miles, Kang Zheng, Rocío Gallego-Durán, Ángela Rojas, Javier Ampuero, Manuel Romero-Gómez, Kaye Philip, Isioma U Egbuniwe, Chaobo Chen, Jorge Simon, Teresa C Delgado, María Luz Martínez-Chantar, Jie Sun, Johanna Reissing, Tony Bruns, Arantza Lamas-Paz, Manuel Gómez Del Moral, Marius Maximilian Woitok, Javier Vaquero, José R Regueiro, Christian Liedtke, Christian Trautwein, Rafael Bañares, Francisco Javier Cubero, Yulia A Nevzorova
• Journal: Cancers (Cancers (Basel)) Vol. 14 Issue 1 (Dec 31 2021) ISSN: 2072-6694 [Print] Switzerland
• PMID: 35008356 (Publication Type: Journal Article)