LIM Homeobox-2 Suppresses Hallmarks of Adult and Pediatric Liver Cancers by Inactivating MAPK/ERK and Wnt/Beta-Catenin Pathways

• DOI: 10.1159/000521595
• Publication Date: 2021-12-21T22:00:36Z
• Authors: Nicola Mosca; Fatma Zohra Khoubai; Sandrine Fedou; Juan Carrillo-Rei...; Stefano Caruso; Alvaro Del Rio-Al...; Emeric Dubois; Christophe Avignon; Nathalie Dugot-Se...; Catherine Guettier; Charlotte Mussini; Jessica Zucman-Rossi; Carolina Armengol; Pierre Thiébaud; Philippe Veschambre; Christophe Franço...
• Keywords: Hepatoblastoma; 0301 basic medicine; Hepatocellular carcinoma; Wnt pathway; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; LHX2; MAPK; LHX2 ; Hepatocellular carcinoma ; MAPK/ERK pathway ; Wnt pathway ; Hepatoblastoma ; Research Article; 3. Good health; 03 medical and health sciences; ERK pathway; Hepatoblastoma; Hepatocellular carcinoma; LHX2; MAPK/ERK pathway; Wnt pathway; RC254-282

<b><i>Introduction:</i></b> Hepatocellular carcinoma and hepatoblastoma are two liver cancers characterized by gene deregulations, chromosomal rearrangements, and mutations in Wnt/beta-catenin (Wnt) pathway-related genes. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis and liver development. LHX2 is oncogenic in many solid tumors and leukemia, but its role in liver cancer is unknown. <b><i>Methods:</i></b> We analyzed the expression of <i>LHX2</i> in hepatocellular carcinoma and hepatoblastoma samples using various transcriptomic datasets and biological samples. The role of LHX2 was studied using lentiviral transduction, in vitro cell-based assays (growth, migration, senescence, and apoptosis), molecular approaches (phosphokinase arrays and RNA-seq), bioinformatics, and two in vivo models in chicken and <i>Xenopus</i> embryos. <b><i>Results:</i></b> We found a strong connection between LHX2 downregulation and Wnt activation in these two liver cancers. In hepatoblastoma, LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors, and low patient survival. Forced expression of LHX2 reduced the proliferation, migration, and survival of liver cancer cells in vitro through the inactivation of MAPK/ERK and Wnt signals. In vivo, LHX2 impeded the development of tumors in chick embryos and repressed the Wnt pathway in <i>Xenopus</i> embryos. 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 mediated the disassembling of beta-catenin/T-cell factor 4 complex and induced expression of multiple inhibitors of Wnt (e.g., TLE/Groucho) and MAPK/ERK (e.g., DUSPs) pathways. <b><i>Conclusion:</i></b> Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.