Disruption of Growth Hormone Receptor Signaling Abrogates Hepatocellular Carcinoma Development

Abstract

Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancers. It is an aggressive neoplasm with dismal outcome because most of the patients present with an advanced-stage disease, which precludes curative surgical options. Therefore, these patients require systemic therapies that typically induce small improvements in overall survival. Hence, it is crucial to identify new and promising therapeutic targets for HCC to improve the current outcome. The liver is a key organ in the signaling cascade triggered by the growth hormone receptor (GHR). Previous studies have shown that GHR signaling stimulates the proliferation and regeneration of liver cells and tissues; however, a definitive role of GHR signaling in HCC pathogenesis has not been identified. 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. 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. Graphical Abstract: Keywords: hepatocellular carcinoma, growth hormone receptor, Ghr knockout mouse, diethylnitrosamine