A novel rexinoid agonist, UAB116, decreases metastatic phenotype in hepatoblastoma by inhibiting the Wnt/ß-catenin pathway via upregulation of TRIM29
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/ß-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/ß-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 ß-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/ß-catenin pathway, providing support for further exploration of LXR/RXR agonism as a therapeutic strategy for metastatic HB. Overall design: By creating two groups, we studied the effects of novel rexinoid agonist UAB116 on HLM_2 cells. Group 1 were untreated HLM_2 cells that acted as control, and group 2 HLM_2 cells were treated with 25µM of UAB 116 for 72 hours. RNA extraction was performed to obtain samples for each group, which were then submitted for RNA sequencing analysis, and one sample per condition was processed.