Nicola Mosca1, Fatma Zohra Khoubai1, Sandrine Fedou1,2, Juan Carrillo-Reixach3,4, Stefano Caruso5, Alvaro Del Rio-Alvarez3, Emeric Dubois6, Christophe Avignon7, Nathalie Dugot-Senant8, Catherine Guettier7, Charlotte Mussini7, Jessica Zucman-Rossi5,9, Carolina Armengol3,4, Pierre Thiébaud1,2, Philippe Veschambre1, Christophe François Grosset1. 1. MIRCADE Team, Univ. Bordeaux, Inserm, BMGIC, Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers, U1035, Bordeaux, France. 2. XenoFish, Univ. Bordeaux, Inserm, BMGIC, Biotherapy of Genetic Diseases, Inflammatory Disorders and Cancers, U1035, Bordeaux, France. 3. Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute (IGTP), Program for Predictive and Personalized Medicine of Cancer (PMPPC), Badalona, Spain. 4. CIBER, Hepatic and Digestive Diseases, Barcelona, Spain. 5. Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, INSERM, Functional Genomics of Solid Tumors Laboratory, Paris, France. 6. Montpellier GenomiX, University of Montpellier, CNRS, INSERM, Montpellier, France. 7. Department of Pathology, Bicêtre University Hospital, University of Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France. 8. Plateforme d'histopathologie Inserm, US 005 - UMS3427 - TBMCore, Bordeaux, France. 9. Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France.
Abstract
Introduction: 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. Methods: We analyzed the expression of LHX2 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 Xenopus embryos. Results: 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 Xenopus 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. Conclusion: Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.
Introduction: 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. Methods: We analyzed the expression of LHX2 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 Xenopus embryos. Results: 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 Xenopus 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. Conclusion: Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.
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Authors: Emilie Indersie; Sarah Lesjean; Katarzyna B Hooks; Francis Sagliocco; Tony Ernault; Stefano Cairo; Maria Merched-Sauvage; Anne Rullier; Brigitte Le Bail; Sophie Taque; Michael Grotzer; Sophie Branchereau; Catherine Guettier; Monique Fabre; Laurence Brugières; Martin Hagedorn; Marie-Annick Buendia; Christophe F Grosset Journal: Hepatol Commun Date: 2017-04-06