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| Status |
Public on Aug 05, 2019 |
| Title |
IGF2 is an epi-driver and therapeutic target in hepatocellular carcinoma |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Background & Aims: Hepatocellular carcinoma (HCC) is a major health problem. Most patients are diagnosed at advanced stages when the only approved therapy is sorafenib. Consequently, there is an urgent need to develop effective treatments. IGF-signaling is aberrantly activated in HCC, but there is no clear understanding on the molecular drivers and potential therapeutic targets within the pathway. Since IGF2-ligand is overexpressed in HCC, we aimed to elucidate its mechanism of overexpression, assess its oncogenic potential in vitro and in vivo and determine the antitumoral efficacy of molecular therapies against IGF2. Methods: Expression profiling, miRNAs expression and methylation were analyzed in 228 HCCs focusing on IGF2. Stable HCC cell lines with knock-down and ectopic overexpression of IGF2 were generated. A chemically-induced mouse model of HCC, and genetically-engineered mouse models (GEMM) overexpressing IGF2 in the liver were generated to assess IGF2 oncogenicity. The therapeutic potential of the monoclonal antibody against IGF-ligands (IGF1/2-mAb) and its combination with sorafenib was tested in vitro and in a xenograft model. Results: IGF2-overexpression occurred in 15% of HCC patients as a result of the epigenetic reactivation of IGF2-fetal promoters, mainly through loss of promoter methylation. Re-expression of IGF2 was associated with progenitor cell-like and poorly differentiated HCCs, and with poor prognosis (p<0.0001). In the GEMM model, IGF2-overexpression accelerated HCC progression and reduced survival (p=0.02). Conversely, IGF2-blockage using IGF1/2- mAbs delayed tumor growth and increased survival in vivo (p<0.0001), through antiproliferative and antiangiogenic mechanisms. Conclusions: We propose IGF2 as the first actionable epi-driver in HCC, and IGF1/2-mAbs as a potential targeted therapy in a defined subset of HCC patients. Keywords: IGF2, HCC, epidriver, IGF-pathway, monoclonal antibody, BI 836845.
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| Overall design |
Transcriptomic study of six genetically-engineered mouse models (GEMM) overexpressing IGF2 referenced to three GEMM control
Transcriptomic study of two cell lines: SNU449 and Hep3B. They are treated to overexpress IGF2 or knocked down. Wild type cell lines are also included
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| Contributor(s) |
Martinez-Quetglas I, Pinyol R, Llovet JM |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Aug 06, 2016 |
| Last update date |
Aug 07, 2019 |
| Contact name |
Juanjo Lozano |
| E-mail(s) |
[email protected]
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| Organization name |
CIBEREHD
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| Department |
Plataforma de Bioinformatica
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| Street address |
C/ Rosselló 153
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| City |
Barcelona |
| ZIP/Postal code |
08036 |
| Country |
Spain |
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| Platforms (2) |
| GPL6887 |
Illumina MouseWG-6 v2.0 expression beadchip |
| GPL13667 |
[HG-U219] Affymetrix Human Genome U219 Array |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA338010 |
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