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Liver Cancer
2021 Dec 21;112:126-140. doi: 10.1159/000521595.
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LIM Homeobox-2 Suppresses Hallmarks of Adult and Pediatric Liver Cancers by Inactivating MAPK/ERK and Wnt/Beta-Catenin Pathways.
Mosca N
,
Khoubai FZ
,
Fedou S
,
Carrillo-Reixach J
,
Caruso S
,
Del Rio-Alvarez A
,
Dubois E
,
Avignon C
,
Dugot-Senant N
,
Guettier C
,
Mussini C
,
Zucman-Rossi J
,
Armengol C
,
Thiébaud P
,
Veschambre P
,
Grosset CF
.
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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.
Bayard,
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress.
2018, Pubmed
Bayard,
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress.
2018,
Pubmed
Boyault,
Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.
2007,
Pubmed
Buendia,
Unravelling the genetics of hepatoblastoma: few mutations, what else?
2014,
Pubmed
Cairo,
Hepatic stem-like phenotype and interplay of Wnt/beta-catenin and Myc signaling in aggressive childhood liver cancer.
2008,
Pubmed
Carrillo-Reixach,
Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications.
2020,
Pubmed
Coker,
canSAR: update to the cancer translational research and drug discovery knowledgebase.
2019,
Pubmed
Cusimano,
Potentiation of the antitumor effects of both selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors in human hepatic cancer cells by inhibition of the MEK/ERK pathway.
2007,
Pubmed
Doucet-Beaupré,
Cell fate determination, neuronal maintenance and disease state: The emerging role of transcription factors Lmx1a and Lmx1b.
2015,
Pubmed
Edgar,
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository.
2002,
Pubmed
Eichenmüller,
The genomic landscape of hepatoblastoma and their progenies with HCC-like features.
2014,
Pubmed
Eicher,
Effect of sorafenib combined with cytostatic agents on hepatoblastoma cell lines and xenografts.
2013,
Pubmed
Genz,
Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells.
2014,
Pubmed
Ghousein,
miR-4510 blocks hepatocellular carcinoma development through RAF1 targeting and RAS/RAF/MEK/ERK signalling inactivation.
2020,
Pubmed
Hirsch,
BAP1 mutations define a homogeneous subgroup of hepatocellular carcinoma with fibrolamellar-like features and activated PKA.
2020,
Pubmed
Hooks,
New insights into diagnosis and therapeutic options for proliferative hepatoblastoma.
2018,
Pubmed
Hsu,
Lhx2 regulates the timing of β-catenin-dependent cortical neurogenesis.
2015,
Pubmed
Huang,
DUSPs, to MAP kinases and beyond.
2012,
Pubmed
Indersie,
Tracking cellular and molecular changes in a species-specific manner during experimental tumor progression in vivo.
2018,
Pubmed
Indersie,
MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β-catenin and Wnt signaling.
2017,
Pubmed
Kolterud,
Lhx2 is expressed in the septum transversum mesenchyme that becomes an integral part of the liver and the formation of these cells is independent of functional Lhx2.
2004,
Pubmed
Kuzmanov,
LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.
2014,
Pubmed
Liang,
MicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/β-catenin signaling pathway by down-regulating LHX2.
2019,
Pubmed
Llovet,
Hepatocellular carcinoma.
2016,
Pubmed
Llovet,
Advances in targeted therapies for hepatocellular carcinoma in the genomic era.
2015,
Pubmed
Meyers,
Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.
2017,
Pubmed
Miyashita,
Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels.
2018,
Pubmed
Nathalia,
Downregulation of tumor-suppressor gene LHX6 in cancer: a systematic review.
2018,
Pubmed
Pez,
Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs.
2013,
Pubmed
Porter,
Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development.
1997,
Pubmed
Ramakrishnan,
The Wnt Transcriptional Switch: TLE Removal or Inactivation?
2018,
Pubmed
Rauscher,
Exploring DNA methylation changes in promoter, intragenic, and intergenic regions as early and late events in breast cancer formation.
2015,
Pubmed
Rebouissou,
Genotype-phenotype correlation of CTNNB1 mutations reveals different ß-catenin activity associated with liver tumor progression.
2016,
Pubmed
Shi,
miR-1238 inhibits cell proliferation by targeting LHX2 in non-small cell lung cancer.
2015,
Pubmed
Sumazin,
Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.
2017,
Pubmed
Valanejad,
PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma.
2018,
Pubmed
Wandzioch,
Lhx2-/- mice develop liver fibrosis.
2004,
Pubmed
Wang,
LIM homeobox transcription factors, a novel subfamily which plays an important role in cancer (review).
2014,
Pubmed
Wang,
Forfeited hepatogenesis program and increased embryonic stem cell traits in young hepatocellular carcinoma (HCC) comparing to elderly HCC.
2013,
Pubmed
Wu,
Transcriptional activation of human LIM-HOX gene hLH-2 in chronic myelogenous leukemia is due to a cis-acting effect of Bcr-Abl.
1997,
Pubmed
Zhang,
Fezf2 promotes neuronal differentiation through localised activation of Wnt/β-catenin signalling during forebrain development.
2014,
Pubmed
,
Xenbase
Zhang,
ICAT inhibits glioblastoma cell proliferation by suppressing Wnt/β-catenin activity.
2015,
Pubmed
Zhou,
Oncogenicity of LHX2 in pancreatic ductal adenocarcinoma.
2014,
Pubmed
de La Coste,
Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas.
1998,
Pubmed
von Schweinitz,
Hepatoblastoma: recent developments in research and treatment.
2012,
Pubmed
