Journal
LIVER CANCER
Volume 11, Issue 2, Pages 126-140Publisher
KARGER
DOI: 10.1159/000521595
Keywords
Hepatocellular carcinoma; Hepatoblastoma; LHX2; Wnt pathway; MAPK; ERK pathway
Categories
Funding
- Investments for the future Programme IdEx Bordeaux [ANR-10-IDEX-03-02]
- Fondation Groupama pour la Sante
- Groupama Centre-Atlantique
- la Ligue Nationale contre le Cancer
- Region Nouvelle-Aquitaine [2018-1R30114]
- France Genomique National program as part of the Investissement d'Avenir program [ANR-10-INBS-09]
- National du Cancer (INCa) [2020-012]
- SFCE
- Etoile de Martin
- FES
- Hubert
- INSERM
- HTE (Cancer plan)
- Ligue Nationale contre le Cancer (Equipe Labellisee)
- Labex OncoImmunology (investissement d'avenir)
- IREB grant
- Coup d'Elan de la Fondation Bettencourt-Schueller
- SIRIC CARPEM
- FRM Rosen award
- Ligue Contre le Cancer Comite de Paris (Rene et Andre Duquesne award)
- Fondation Merieux
- Labex OncoImunology
- CARPEM
- Catalan Agency for the Management of University and Research Grants (AGAUR) [2019 FI_ B01024]
- Instituto de Salud Carlos III [PI10/02082, PI13/02340]
- European Union [668596]
- CIBERehd [CB06/04/0033]
- AGAUR [2017SGR-490]
- Spanish Ministry of Science and Innovation [RYC-2010-07249]
- H2020 Societal Challenges Programme [668596] Funding Source: H2020 Societal Challenges Programme
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This study demonstrates that LHX2 is downregulated in hepatocellular carcinoma and hepatoblastoma, and its downregulation is associated with Wnt pathway activation. Furthermore, overexpression of LHX2 inhibits the proliferation, migration, and survival of liver cancer cells by inactivating MAPK/ERK and Wnt signals. The findings suggest that LHX2 acts as a tumor suppressor 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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