Resumen de The role of oncogene c-MYC in the development and progression of non-alcoholic fatty liver disease in mice
- español
La enfermedad del hígado graso no alcohólico (NAFLD) se ha convertido rápidamente en una de las principales etiologías del HCC y representa un gran problema social y de salud. Muchos factores son responsables del alto riesgo de desarrollar HCC relacionado con NAFLD. Últimamente, se ha sugerido que los oncogenes son determinantes. La activación oncogénica dec-MYC puede inducir inestabilidad genética, promover el ciclo celular y aumentar la proliferación, acelerando así la progresión tumoral, los estudios también observaron una sobreexpresión significativa de c-MYC en hígados con CLD, incluida la hepatitis hepática, fibrosis y cirrosis, y también indica la sobreexpresión de c-MYC podría aumentar la susceptibilidad de las células hepáticas a desarrollar HCC; sin embargo, su papel aún se desconoce. Engeneral, nuestro objetivo fue analizar el impacto del protooncogén c-MYC en el desarrollo de HCC asociado a NAFLD murino...
- español
Introduction Nonalcoholic fatty liver disease (NAFLD) has rapidly risen as one of the leading etiologies for HCC and represents a large societal and health problem. Many factors are responsible for the high risk of NAFLD and NAFLD-related HCC development. Lately, oncogenes have been suggested to be determinant. The oncogene activation of c-MYC can induce genetic instability, promote the cell cycle, and increase proliferation, thereby accelerating tumor progression, studies also observed a significant c-MYC overexpression in livers with CLD including hepatic hepatitis, fibrosis and cirrhosis, and also indicates the overexpression of c-MYC might increase the susceptibility of liver cells to develop HCC; however, their role still remains unknown. Here we overall aimed to analyse the impact of the proto-oncogene c-MYC in the development of murine NAFLD and NAFLD-associated HCC.
Methods Transgenic mice bearing overexpression of c-MYC in hepatocytes (Alb-myctg) were studied at baseline conditions (36 weeks, 1 year) as well as after application of 24w or 40w of Western diet (WD). WT mice were used as control mice. At the experiment timepoint respectively, mice were sacrificed, liver and epidydimal white adipose tissue (eWAT) were collected. Hispathological examination of liver and eWAT, immunofluorescense (IF) and immunohistochemistry (IHC), Western blot and Real time-qPCR studies were performed. The expression of c-MYC in patients with NAFLD was also evaluated.
Results Mild obesity, spontaneous hyperlipidaemia, glucose intolerance and insulin resistance were characteristic of 36-week-old Alb-myctg mice. Moreover, middle-aged Alb-myctg mice exhibited macrovesicular steatosis, hepatocellular ballooning and increased triglyceride content, compared to WT littermates. Liver injury and inflammation associated with elevated serum transaminases, up-regulation of the ER-stress response and ROS production, significant collagen accumulation and compensatory proliferation was apparent in transgenic animals at 36 weeks. In agreement with earlier studies, 20% of Alb-myctg mice developed HCC at 1 year of age. Importantly, the application of WD exacerbated metabolic abnormalities, steatohepatitis, fibrogenesis and substantially enhanced the tumor incidence.
