A Shortcut from Metabolic-Associated Fatty Liver Disease (MAFLD) to Hepatocellular Carcinoma (HCC): c-MYC a Promising Target for Preventative Strategies and Individualized Therapy
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 strategiesMINECO Retos SAF2016-78711SAF2017-87919-RPID2020-117827RB-IOOPID2020-117941RB-IOOPID2020-117116RB-I00EXOHEP-CM S2017/BMD- 3727NanoLiver-CM Y2018/NMT-4949AMMF 2018/117COST Action CA17112UCM-25/2019La Caixa Foundation Program HR17-00601Asociación Española Contra el Cáncer AECC PROYE20084 REGUthe German Research Foundation SFB1382 Project ID 403224013/A02Ramón y Cajal Researchers RYC-2014-15242RYC-2015-17438Instituto de Salud Carlos III PI16/01842, PI19/01404; PI19/00589The German Research Foundation SFB1382 Project ID 403224013/B0
