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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109605 | GEO | 2018/03/19

REPOSITORIES: GEO

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

Project description:The oncofetal IGF2 mRNA binding proteins (IGF2BPs) are upregulated in most cancers but their paralogue-specific roles in tumor cells remain poorly understood. In a panel of five cancer-derived cell lines, IGF2BP1 shows highly conserved oncogenic potential. Consistently, the deletion of IGF2BP1 impairs the growth and metastasis of ovarian cancer-derived cells in nude mice. Gene expression analyses in ovarian cancer-derived cells reveal that the knockdown of IGF2BPs is associated with the downregulation of mRNAs that are prone to miRNA regulation. All three IGF2BPs preferentially associate upstream of miRNA binding sites (MBSs) in the 3'UTR of mRNAs. The downregulation of mRNAs co-regulated by miRNAs and IGF2BP1 is abrogated at low miRNA abundance or when miRNAs are depleted. IGF2BP1 associates with these target mRNAs in RISC-free complexes and its deletion enhances their association with AGO2. The knockdown of most miRNA-regulated target mRNAs of IGF2BP1 impairs tumor cell properties. In four primary cancers, elevated synthesis of these target mRNAs is largely associated with upregulated IGF2BP1 mRNA levels. In ovarian cancer, the enhanced expression of IGF2BP1 and most of its miRNA-controlled target mRNAs is associated with poor prognosis. In conclusion, these findings indicate that IGF2BP1 enhances an aggressive tumor cell phenotype by antagonizing miRNA-impaired gene expression.

| S-EPMC6158595 | biostudies-literature

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

Project description: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.

2018-03-19 | GSE109604 | GEO

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

Project description: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. The downregulation of target mRNAs observed upon IGF2BP1 depletion is abrogated when miRNAs are expressed at low levels or depleted by DICER/DROSHA knockdown. Strikingly, the depletion of 10 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.

2018-03-19 | GSE109422 | GEO

IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [HUH-7 small RNA]

2018-03-19 | GSE109677 | GEO

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

Project description:IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors

| PRJNA431456 | ENA

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

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

| PRJNA431461 | ENA

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

Project description:IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [small RNA]

| PRJNA430865 | ENA

IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [HUH-7 small RNA]

Project description:IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors [HUH-7 small RNA]

| PRJNA431640 | ENA

Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells.

Project description:Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).

| S-EPMC8794255 | biostudies-literature

A miRNA signature for defining aggressive phenotype and prognosis in gliomas.

Project description:Gliomas represent a disparate group of tumours for which there are to date no cure. Thus, there is a recognized need for new diagnostic and therapeutic approaches based on increased understanding of their molecular nature. We performed the comparison of the microRNA (miRNA) profile of 8 WHO grade II gliomas and 24 higher grade tumours (2 WHO grade III and 22 glioblastomas) by using the Affymetrix GeneChip miRNA Array v. 1.0. A relative quantification method (RT-qPCR) with standard curve was used to confirm the 22 miRNA signature resulted by array analysis. The prognostic performances of the confirmed miRNAs were estimated on the Tumor Cancer Genome Atlas (TCGA) datasets. We identified 22 miRNAs distinguishing grade II gliomas from higher grade tumours. RT-qPCR confirmed the differential expression in the two patients' groups for 13 out of the 22 miRNAs. The analysis of the Glioblastoma Multiforme (GBM) and Lower Grade Glioma (LGG) datasets from TCGA demonstrated the association with prognosis for 6 of those miRNAs. Moreover, in the GBM dataset miR-21 and miR-210 were predictors of worse prognosis in both univariable and multivariable Cox regression analyses (HR 1.19, p = 0.04, and HR 1.18, p = 0.029 respectively). Our results support a direct contribution of miRNAs to glioma cancerogenesis and suggest that miR-21 and miR-210 may play a role in the aggressive clinical behaviour of glioblastomas.

| S-EPMC4184816 | biostudies-literature

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