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Functional antagonism between Mir483 and its host gene Igf2 in the control of developmental growth

ABSTRACT: Many mammalian microRNAs are embedded within introns of protein-coding genes, yet their functional relationship with the host gene is poorly understood. Here we identify Mir483, as having opposing developmental and physiological roles to those of its host gene, the paternally-expressed Igf2. Mechanistically, Mir483 expression is dependent on Igf2 transcription and the epigenetic regulation of the Igf2/H19 imprinting control region. Mir483 deletion in vivo resulted in normal growth, but induced distinct molecular signatures. Transgenic Mir483 overexpression in utero caused fetal, but not placental, growth restriction and cardiovascular defects leading to fetal demise. Overexpression of Mir483 postnatally resulted in growth stunting through IGF1 repression, increased hepatic lipid production, and excessive adiposity. IGF1 infusion rescued the post-natal growth restriction. Our data highlight a novel functional antagonism between a growth-suppressor microRNA and its growth-promoting host gene. We suggest that Mir483 was evolutionary co-opted to provide exquisite control of IGF signalling activity.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryo

SUBMITTER: Robin Antrobus

LAB HEAD: Miguel Constância

PROVIDER: PXD051516 | Pride | 2024-09-12

REPOSITORIES: Pride

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			Action	DRS
	WC_TMT_120913_proteinGroups.txt	Txt
	WC_TMT_sax11_100913_run1.raw	Raw
	WC_TMT_sax3_100913_run1.raw	Raw
	WC_TMT_sax4_100913_run1.raw	Raw
	WC_TMT_sax5_100913_run1.raw	Raw

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Project description: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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