The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB

Schmiedel, Dominik; Tai, Julie; Yamin, Rachel; Berhani, Orit; Bauman, Yoav; Mandelboim, Ofer

doi:10.7554/elife.13426

Cited by 42 publications

(37 citation statements)

References 65 publications

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“…We thus analyzed a relatively small but highly homogenous cohort of patients and corroborated clinical data with functional studies in patient-derived cell lines and/or IGF2BP3-silenced cells, in vitro and in vivo, to demonstrate that IGF2BP3 acts as a potent promoter of Ewing sarcoma malignancy. Several studies have described elevated expression of IGF2BP3 in human cancers, including osteosarcoma and leiomyosarcoma (38,45), and provided evidence that IGF2BP3 plays essential roles in the modulation of tumor cell fate, stemness, migration, metastasis, and immune escape (46). Studies recently performed in immortalized hMSCs have demonstrated IGF2BPs within a dicer-resistant set of genes with a pan-cancer relevance in tumor development (47).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Mancarella

Pasello

Ventura

et al. 2018

Clinical Cancer Research

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Large-scale sequencing studies have indicated that besides genomic alterations, the posttranscriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma. We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of Ewing sarcoma aggressiveness. Explorative study was performed in 14 patients with localized Ewing sarcoma using RNA sequencing. Next, 128 patients with localized Ewing sarcoma were divided into two cohorts. In the training set, 29 Ewing sarcoma samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 Ewing sarcoma samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.Univariate and multivariate analyses indicated as a potent indicator of poor prognosis. Furthermore, mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of and could identify different patient outcomes-high and low levels indicated poor survival (25%), whereas low and high levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of Ewing sarcoma cells to grow under anchorage-independent conditions. The combined assessment of and predicts recurrence in Ewing sarcoma patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated. .

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Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Mancarella

Pasello

Ventura

et al. 2018

Clinical Cancer Research

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“…By binding different mRNAs, IGF2BPs decide the fate of those mRNAs by controlling their localization, stability, and translation [40]. Many studies have reported the role of IGF2BPs in cell proliferation, cell invasion, tumorigenesis, and embryogenesis [40][41][42][43][44][45][46][47][48][49][50][51]. IGF2BPs have also been found in sheep trophoblast cells suggesting their role in rapid proliferation of these cells [52].…”

Section: Introductionmentioning

confidence: 99%

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

Ali

Stenglein

Spencer

et al. 2020

IJMS

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LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which significantly decreased let-7 miRNAs and increased IGF2BP1-3, HMGA1, ARID3B, and c-MYC compared to control. This is the first study showing the role of the LIN28-let-7 axis in trophoblast proliferation and conceptus elongation in vivo. These results suggest that reduced LIN28 during early placental development can lead to reduced trophoblast proliferation and sheep conceptus elongation at a critical period for successful establishment of pregnancy.

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“…NK cells were purified and activated as previously described (47). For FACS-based determination of NK cell degranulation, 1 ϫ 10 5 NK cells were incubated without target cells or with 5 ϫ 10 4 SupT1 cells infected with Z29 for 12, 14, 16, or 22 h. For the blocking of activating receptors on NK cells, 0.25 g per well of antibody targeting NKG2D (R&D Systems) or NKp30 (Biolegend), or both antibodies simultaneously, was added prior to the experimental setup and incubated for 60 min on ice.…”

Section: Methodsmentioning

confidence: 99%

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

Schmiedel

Tai

Levi‐Schaffer

et al. 2016

J Virol

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The Herpesviridae family consists of eight viruses, most of which infect a majority of the human population. One of the lessstudied members is human herpesvirus 6 (HHV-6) (Roseolovirus), which causes a mild, well-characterized childhood disease. Primary HHV-6 infection is followed by lifelong latency. Reactivation frequently occurs in immunocompromised patients, such as those suffering from HIV infection or cancer or following transplantation, and causes potentially life-threatening complications. In this study, we investigated the mechanisms that HHV-6 utilizes to remain undetected by natural killer (NK) cells, which are key participants in the innate immune response to infections. We revealed viral mechanisms which downregulate ligands for two powerful activating NK cell receptors: ULBP1, ULBP3, and MICB, which trigger NKG2D, and B7-H6, which activates NKp30. Accordingly, this downregulation impaired the ability of NK cells to recognize HHV-6-infected cells. Thus, we describe for the first time immune evasion mechanisms of HHV-6 that protect lytically infected cells from NK elimination. IMPORTANCEHuman herpesvirus 6 (HHV-6) latently infects a large portion of the human population and can reactivate in humans lacking a functional immune system, such as cancer or AIDS patients. Under these conditions, it can cause life-threatening diseases. To date, the actions and interplay of immune cells, and particularly cells of the innate immune system, during HHV-6 infection are poorly defined. In this study, we aimed to understand how cells undergoing lytic HHV-6 infection interact with natural killer (NK) cells, innate lymphocytes constituting the first line of defense against viral intruders. We show that HHV-6 suppresses the expression of surface proteins that alert the immune cells by triggering two major receptors on NK cells, NKG2D and NKp30. As a consequence, HHV-6 can replicate undetected by the innate immune system and potentially spread infection throughout the body. This study advances the understanding of HHV-6 biology and the measures it uses to successfully escape immune elimination. Human herpesvirus 6 (HHV-6) (Roseolovirus) was long neglected in research and medical diagnostics; however, in the past few years, it gained increasing attention. A variety of clinical complications were found to be associated with HHV-6 infection, especially concerning immunocompromised patients, in whom it has the ability to cause severe morbidity and mortality (1, 2). HHV-6 is subclassified into two distinct variants, HHV-6A and HHV-6B, which are considered independent viruses but share major genome sequence homologies and epidemiologies (3,4). Similarly to other members of the herpesvirus family, HHV-6 causes a relatively short and mild primary disease called roseola infantum, usually in children up to the age of 2 years, with a sudden rise of fever and rash as major symptoms (5). Following this initial infection, HHV-6 establishes lifelong latency in about 90% of all individuals examined (2). Reactivation frequentl...

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The RNA binding protein IMP3 facilitates tumor immune escape by downregulating the stress-induced ligands ULPB2 and MICB

Cited by 42 publications

References 65 publications

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

Human Herpesvirus 6B Downregulates Expression of Activating Ligands during Lytic Infection To Escape Elimination by Natural Killer Cells

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