SAT-LB054 Growth Hormone Receptor (GHR) Antagonism Suppresses Hepatocellular Carcinoma Growth in a Syngeneic Mouse Model

The incidence of hepatocellular carcinoma (HCC) or hepatoma has steadily increased over the past few decades with the ever-increasing prevalence of both Hepatitis -B and -C viral infections and chronic liver diseases. Human HCC tumor cells express growth hormone receptors (GHRs). It has been shown that GHR signaling is important for the metabolism and progression of more than ten human cancers including breast cancer and melanoma. We hypothesized that growth hormone (GH) induced signaling is important for cell growth and metabolism in HCC. Therefore, GHR antagonism will inhibit the progression of malignancy both in vitro and in vivo. To test this hypothesis, we used a syngeneic mouse model using Hepa-1-6 murine HCC cells in C57BL6/J mice and assayed cell proliferation along with western blotting (WB), ELISA, and RT-qPCR of several genes. We observed that GHR-expressing Hepa1-6 mouse hepatoma cells had a significantly upregulated proliferative response to GH treatment. This result could be attributed to GH alone, or to both, GH and insulin-like growth factor-1 (IGF-1). We found that both IGF-1 protein and mRNA levels in Hepa1-6 cells remained unaffected irrespective of GH concentrations. Cells also failed to exhibit the same proliferative response to IGF-1 as seen with GH treatment, further substantiating the IGF-1-independent growth-promoting role of GH in the progression of HCC. To evaluate the effects of GH on the development and progression of HCC in vivo, Hepa-1-6 cells were subcutaneously inoculated into both a transgenic mouse model expressing a growth hormone antagonist (GHA) with characteristically decreased circulating IGF-1 levels but supraphysiological GH levels, and WT controls. Subsequent tumor growth was evaluated and a decreased tumor size in GHA animals was observed. Moreover, excised tumors from the GHA mice were significantly smaller by mass than those found in their WT counterparts. These results suggest a therapeutic role for GHA in offsetting the pro-tumorigenic effects of GH action on HCCs in mice. Further studies are ongoing to elucidate the effects of GH antagonism on HCC in vitro and in vivo, on specific processes like Epithelial-to-mesenchymal transition (EMT) and drug efflux. Our preliminary results implicate GH inhibition as a prospective therapeutic agent against the progression of HCC. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.