Myeloid differentiation primary response protein 88 (Myd88) knockout mice are more susceptible to develop liver cancer

HEIT-BARBINI, FJ; COMANZO, CG; VERA, MC; LORENZETTI, F; LUCCI, A; FERRETTI, AC; CEBALLOS, MP; ALVAREZ ML; CARRILLO, MC; QUIROGA, AD

Congreso; SAFIS; 2019

Inflammation is an important component of tumorigenesis. Myd88 is involved in Toll-like receptor and IL-1 receptor signaling pathways in the innate immuneresponse. We claim that signaling through Myd88 plays a key role in liver cancer development in mice. Adult C57BL/6 wild-type (WT) and Myd88-/- mice (23-25 g) were subject to a model of early liver cancer development. This was induced by administration of 2 i.p. doses of diethylnitrosamine (75 mg/kg bw) 2 weeks apart. One week after the last injection, mice received 20 mg/kg bw of 2-acetylaminofluorene by gastric probe 3 days a week for 3 weeks. All studies were performed before the initiation of treatment and showed no difference between genotypes. After cancer development, Myd88-/- mice showed lower body but higher liver weights than WT mice. We confirmed the complete absence of liver Myd88 protein expression by immunoblotting, as well as Myd88 mRNA expression, when evaluated by qPCR. Liver histology analysis showed scatter alterations on hepatocyte architecture, with accumulation of cytosolic lipid droplets (+23%) and increased inflammatory infiltration (+45%) in Myd88-/- mice compared to WT mice. Hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were slightly increased (+15%, and +12%, respectively) in plasma of Myd88-/- mice compared to WT mice, indicating a mild liver damage. Then, we evaluated proliferation and apoptosis by immunoblotting. We found that Myd88-/- mice presented with decreased protein expression of proliferation cell nuclear antigen (PCNA) (-35%), with a slight decrease in caspase-3 expression and no changes in Bax and cytochrome c expressions in total liver homogenates. These studies represent the first steps in the evaluation of the role of Myd88 in liver cancer development, and demonstrate that Myd88 is involved in prevention of chemical hepatocarcinogenesis; exposing, once again, the tight relationship between the immune system and the de development of cancer.