LIM homeobox-2 suppresses hallmarks of adult and pediatric liver cancers by controlling MAPK/ERK and Wnt/beta-catenin pathways
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ABSTRACT:
PROVIDER: PRJNA674868 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12994800.fastq.gz | Fastqsanger.gz | |||
| SRR12994795.fastq.gz | Fastqsanger.gz | |||
| SRR12994796.fastq.gz | Fastqsanger.gz | |||
| SRR12994797.fastq.gz | Fastqsanger.gz | |||
| SRR12994798.fastq.gz | Fastqsanger.gz |
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Project description: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/β-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.
2023-11-01 | GSE160939 | GEO
Project description:IntroductionHepatocellular 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.MethodsWe 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.ResultsWe 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.ConclusionCollectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.
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Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
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Project description:The mammalian genome contains two ERK/MAP kinase kinase genes, Mek1 and Mek2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. To define the function of ERK/MAPK signaling pathway in lung development, we performed tissue-specific deletions of Mek1 function in a Mek2 null background. Inactivation of both Mek genes in mesenchyme resulted in several phenotypes including giant omphalocele, skeletal defects, pulmonary hypoplasia, abnormal trachea patterning, and death at birth. Microarray analysis with RNA extracted from lungs of E15.5 Dermo1+/Cre, Mek1+/flox;Mek2-/-;Dermo1+/Cre and Mek1flox/flox;Mek2-/-;Dermo1+/Cre embryos was performed to evaluate the molecular impact of the loss of all Mek alleles in mesenchyme on lung development. .
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