GSE160939
LIM homeobox-2 suppresses hallmarks of adult and pediatric liver cancers by controlling MAPK/ERK and Wnt/beta-catenin pathways
Hepatocellular carcinoma (HCC) and Hepatoblastoma (HB) are two liver cancers characterized by high gene deregulation, chromosomal rearrangements and typical mutations in genes related to the Wnt/ß-catenin (Wnt) pathway. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis, liver development but also tumorigenesis. LHX2 is an oncogene in may solid tumors and leukemia but its role in liver cancer is unknown. To address this question we analyzed the expression of LHX2 in HCC and HB using various transcriptomic datasets and found a strong connection between LHX2 down-regulation and Wnt activation in these two liver cancers. In HB LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors and patients' survival. A forced expression of LHX2 reduced the proliferation, the migration and the survival of hepatoma cells in vitro through the inactivation of MAPK/ERK and Wnt signalings. In vivo, LHX2 impeded the development of tumors in the chick embryo and repressed the Wnt pathway in Xenopus embryo. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 induced the disassembling of beta-catenin and T-cell factor 4 and the expression of multiple inhibitors of Wnt (e.g. TLE/Groucho) and MAPK/ERK (e.g. DUSPs) pathways. Collectively, our findings demonstrate the tumor suppressive function of LHX2 in adult and pediatric liver cancers. Overall design: Transcriptome profile in Huh7 cell overexpressing LHX2 vs CTRL cells