ABSTRACT: Hepatoblastoma (HB) is the most common pediatric primary liver tumor. About 20% of children have pulmonary metastasis at presentation. Survival rates for these children are dismal, not exceeding 25%. To study this subset of the HB population, we sequenced a metastatic HB cell line, HLM_2, and identified a downregulation in the liver X receptor (LXR)/rexinoid X receptor (RXR) pathway. LXR/RXRs are transcriptional regulators of genes involved in HB carcinogenesis including the Wnt/β-catenin signaling pathway. We assessed the effects of a novel LXR/RXR agonist, UAB116, on metastatic HB, hypothesizing that this compound would affect genes governing the Wnt/β-catenin pathway, leading to decreased metastatic phenotype in HLM_2 metastatic HB cells. We evaluated the effects on viability, proliferation, stemness, clonogenicity, and motility, and performed RNA sequencing to study differential gene regulation. Treatment with UAB116 (0-50 µM) for 72 hours decreased HLM_2 proliferation, stemness, clonogenicity, and invasion. RNA sequencing identified an 8-fold increase in TRIM29, a gene known to inhibit β-catenin, in cells treated with UAB116. These results show that treatment with an LXR/RXR agonist, UAB116, decreases metastatic HB cell proliferation, stemness, and invasion, likely through upregulation of TRIM29, a known regulator of the Wnt/β-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB.
