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

HEIT BARBINI, FRANCISCO J.; COMANZO, CARLA G.; VERA MARINA C.; LORENZETTI, FLORENCIA; LUCCI, ALVARO; FERRETTI, ANABELA C.; CEBALLOS, MARÍA P.; CARRILLO, MARÍA C.; QUIROGA, ARIEL D.

Rosario

Congreso; Reunión anual SAFIS 2019 ROSARIO; 2019

Inflammation is an important component oftumorigenesis. Myd88 is involved in Toll-like receptor andIL-1 receptor signaling pathways in the innate immune response. We claim that signaling through Myd88 plays akey role in liver cancer development in mice. AdultC57BL/6 wild-type (WT) and Myd88-/- mice (23-25 g) weresubject to a model of early liver cancer development. Thiswas induced by administration of 2 i.p. doses ofdiethylnitrosamine (75 mg/kg bw) 2 weeks apart. Oneweek after the last injection, mice received 20 mg/kg bwof 2-acetylaminofluorene by gastric probe 3 days a weekfor 3 weeks. All studies were performed before theinitiation of treatment and showed no difference betweengenotypes. After cancer development, Myd88-/- miceshowed lower body but higher liver weights than WT mice.We confirmed the complete absence of liver Myd88protein expression by immunoblotting, as well as Myd88mRNA expression, when evaluated by qPCR. Liverhistology analysis showed scatter alterations onhepatocyte architecture, with accumulation of cytosoliclipid droplets (+23%) and increased inflammatoryinfiltration (+45%) in Myd88-/- mice compared to WTmice. Hepatic enzymes aspartate aminotransferase (AST)and alanine aminotransferase (ALT) were slightlyincreased (+15%, and +12%, respectively) in plasma ofMyd88-/- mice compared to WT mice, indicating a mildliver damage. Then, we evaluated proliferation andapoptosis by immunoblotting. We found that Myd88-/-mice presented with decreased protein expression ofproliferation cell nuclear antigen (PCNA) (-35%), with aslight decrease in caspase-3 expression and no changes inBax and cytochrome c expressions in total liverhomogenates. These studies represent the first steps inthe evaluation of the role of Myd88 in liver cancerdevelopment, and demonstrate that Myd88 is involved inprevention of chemical hepatocarcinogenesis; exposing,once again, the tight relationship between the immunesystem and the de development of cancer.