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IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [mRNA]

ABSTRACT: The oncofetal IGF2 mRNA binding protein (IGF2BP) family modulates tumor cell properties but IGF2BP paralogue-specific roles remain poorly understood. We demonstrate that phenotypic roles of IGF2BPs vary in a cancer cell-dependent manner. However, only IGF2BP1 shows oncogenic potential in all cancer cells analyzed. Consistently, only IGF2BP1 expression is associated with poor prognosis in ovarian carcinoma and promotes all oncogenic properties analyzed in ovarian cancer-derived tumor cells. Despite a substantial overlap of candidate target mRNAs of IGF2BP paralogues proposed by CLIP analyses, the paralogue-specific depletion of IGF2BPs induces strikingly distinct deregulation of mRNA abundance. Transcripts decreased by IGF2BP1 depletion or knockout are enriched for IGF2BP1- as well as AGO-CLIP hits conserved in distinct cell lines, are prone to targeting by highly abundant miRNAs and comprise significantly longer 3’UTRs. Downregulation of target mRNAs upon IGF2BP1 depletion is abrogated when miRNAs are expressed at low levels or depleted by DICER/DROSHA knockdown. Strikingly, the depletion of all 12 randomly selected miRNA-prone target mRNAs impairs at least one analyzed IGF2BP1-modulated tumor cell property. These findings indicate that IGF2BPs serve distinct roles in cancer-derived cells and suggest that IGF2BP1’s main role is the post-transcriptional, miRNome-dependent enhancement of factors promoting oncogenic tumor cell properties.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109604 | GEO | 2018/03/19

REPOSITORIES: GEO

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Project description:Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, and IGF2BP3) are a family of RNA-binding proteins that play an essential role in the development and disease by regulating mRNA stability and translation of critical regulators of cell division and metabolism. Genetic and chemical inhibition of these proteins slows down cancer cell proliferation, decreases invasiveness, and prolongs life span in a variety of animal models. The role of RNA-binding proteins in the induction of tissues’ immunogenicity is increasingly recognized, but, the impact of the IGF2BPs family of proteins on the induction of innate and adaptive immune responses in cancer is not fully understood. Here we report that downregulation of IGF2BP1, 2, and 3 expression facilitates the expression of interferon beta-stimulated genes. IGF2BP1 has a greater effect on interferon beta and gamma signalings compared to IGF2BP2 and IGF2BP3 paralogs. We demonstrate that knockdown or knockout of IGF2BP1, 2, and 3 significantly potentiates inhibition of cell growth induced by IFNβ and IFNγ. Mouse melanoma cells with Igf2bp knockouts demonstrate increased expression of MHC I (H-2) and induce intracellular Ifn-γ expression in syngeneic T-lymphocytes in vitro. Increased immunogenicity, associated with Igf2bp1 inhibition, “inflames” mouse melanoma tumors microenvironment in SM1/C57BL/6 and SW1/C3H mouse models measured by a two-fold increase of NK cells and tumor-associated myeloid cells. Finally, we demonstrate that the efficiency of anti-PD1 immunotherapy in the mouse melanoma model is significantly more efficient in tumors that lack Igf2bp1 expression. Our retrospective data analysis of immunotherapies in human melanoma patients indicates that high levels of IGF2BP1 and IGF2BP3 are associated with resistance to immunotherapies and poor prognosis. In summary, our study provides evidence of the role of IGF2BP proteins in regulating tumor immunogenicity and establishes those RBPs as immunotherapeutic targets in cancer.

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IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [mRNA]

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