Figure 2.

Genetic depletion of ChREBP strongly delays hepatocarcinogenesis driven by AKT overexpression in the mouse. (a) Overexpression of myr-AKT1 promoted the development of multiple liver tumors by 29 weeks post hydrodynamic injection in ChREBP WT mice (indicated as AKT/ChREBP). Macroscopically, livers of AKT/ChREBP mice were enlarged, pale, and characterized by the presence of numerous nodules occupying the whole surface. Microscopically, the liver parenchyma of AKT/ChREBP mice was occupied by large hepatocellular tumors containing areas of necrosis (N). Importantly, tumors displayed a homogeneous immunoreactivity for HA-tagged AKT (insets), implying their origin from hydrodynamically transfected cells. (a; lower panel). (b) In striking contrast, overexpression of AKT in ChREBP KO mice (indicated as AKT/ChREBPKO) resulted in delayed hepatocarcinogenesis at the same time point. Livers of AKT/ChREBKO mice appeared normal macroscopically and displayed the presence of isolated or small clusters of altered cells at the microscopic level. As expected, the scattered altered hepatocytes exhibited immunolabeling for HA-Tagged AKT (inset). (c; left panels). Fifty-two weeks after hydrodynamic injection, a large fraction of AKT/ChREBPKO liver parenchyma was occupied by altered hepatocytes, characterized by a strikingly enlarged cytoplasm. (c; right panels). Furthermore, the liver of three of fifteen (20%) AKT/ChREBPKO mice displayed the presence of tumor nodules macroscopically appreciable (indicated by arrow). Microscopically, the nodular lesions consisted of clear-cell hepatocellular carcinomas. Original magnifications: 40x and 100x. Scale bar: 500µm for 40x, 100µm for 100x. Abbreviations: HE, hematoxylin and eosin; w.p.i., weeks post injection.