Conclusion
Collectively, our data support an important role of GHR in HCC development, and suggest that exploiting GHR signaling may represent a promising approach to treat HCC.
Methods
In this study, we used a direct and specific approach to analyze the role of GHR in HCC development. This approach encompasses mice with global (Ghr-/- ) or liver-specific (LiGhr-/- ) disruption of GHR expression, and the injection of diethylnitrosamine (DEN) to develop HCC in these mice.
Results
Our data show that DEN induced HCC in a substantial majority of the Ghr+/+ (93.5%) and Ghr +/- (87.1%) mice but not in the Ghr-/- (5.6%) mice (P < 0.0001). Although 57.7% of LiGhr-/- mice developed HCC after injection of DEN, these mice had significantly fewer tumors than LiGhr+/+ (P < 0.001), which implies that the expression of GHR in the liver cells might increase tumor burden. Notably, the pathologic, histologic, and biochemical characteristics of DEN-induced HCC in mice resembled to a great extent human HCC, despite the fact that etiologically this model does not mimic this cancer in humans. Our data also show that the effects of DEN on mice livers were primarily related to its carcinogenic effects and ability to induce HCC, with minimal effects related to toxic effects.