NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma

Fiaschetti, Giulio; Schroeder, Christina I.; Castelletti, Deborah; Arcaro, Alexandre; Westermann, Frank; Baumgärtner, Martin; Shalaby, Tarek; Grotzer, Michael A.

doi:10.1186/2051-5960-2-39

Cited by 33 publications

(29 citation statements)

References 46 publications

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“…It has been demonstrated that JAG1 is overexpressed in various types of cancer, and it is involved in several aspects of tumor biology, including cell growth, apoptosis, cancer stem cell maintenance, epithelial-mesenchymal transition and metastasis (38). Fiaschetti et al (39) revealed that JAG1 is overexpressed in the majority of medulloblastoma (MB), and JAG1 is crucial in maintaining Notch-related pro-survival functions in MB cells (39). In the present study, JAG1 expression was demonstrated to be regulated by miR-140-5p in glioma cells.…”

Section: Discussionmentioning

confidence: 99%

miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1

Yang

Gao

Zhao

2017

Molecular Medicine Reports

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miR‑140‑5p has been reported to be a tumor suppressor in several types of human cancer, however, little is known about its expression and function in human gliomas. The present study aimed to detect the expression of miR‑140‑5p in human glioma tissues and cell lines, and to investigate the effect of miR‑140‑5p on glioma cell growth, invasion and adhesion using in vitro gain‑of‑function and loss‑of‑function experiments. Furthermore, the hypothesis that Jagged1 (JAG1) may be a target gene of miR‑140‑5p was tested. Reverse transcription‑quantitative polymerase chain reaction analysis revealed that miR‑140‑5p was significantly downregulated in human glioma tissues and cell lines compared with normal tissues, and that its expression was correlated with the grade of gliomas. Transfection of a miR‑140‑5p mimic into SW1783 glioma cells promoted cell growth, invasion and adhesion, as determined by MTT, Transwell and cell adhesion assays respectively. By contrast, transfection of a miR‑140‑5p inhibitor had the opposite effect. A dual‑luciferase reporter assay confirmed that JAG1 was a target gene of miR‑140‑5p, and miR‑140‑5p inhibited JAG1 expression both at the mRNA and protein level. In addition, JAG1 overexpression reversed the effect of miR‑140‑5p on glioma cell growth, invasion and adhesion. In conclusion, the present study is the first to reveal that miR‑140‑5p acts as a tumor suppressor in human gliomas. JAG1 was demonstrated to be a novel target of miR‑140‑5p, and miR‑140‑5p exerted its inhibitory effect on human glioma growth and invasion, partly by suppressing JAG1. The present study may provide useful information toward novel targets for the treatment of gliomas.

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Section: Discussionmentioning

confidence: 99%

miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1

Yang

Gao

Zhao

2017

Molecular Medicine Reports

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“…All data used are accessible through the open access platform R2 for visualization and analysis of the microarray data ( http://r2.amc.nl ). The following datasets were used: Delattre 54 MAS 5.0 – u133p2 (54 MB samples), Gilbertson 76 MAS 5.0 – u133p2 (76 pediatric MB samples, PubMed link: 22722829), Kool 62 MAS 5.0 – u133p2 (62 human MB samples, PubMed link 18769486), Northcott 103 rma_sketch – huex10t (103 primary MB samples, PubMed link 20823417) and MAGIC 285 rma-sketch – hugene11t (285 primary MB samples, PubMed link 22832581) Analysis was performed as described in (Fiaschetti et al 2014 ). The nine normal cerebellum samples are from human subject aged as follows: Donor 1–25 year old male; donor 2–38 year old male; donor 3–39 year old female; donor 4–30 year old male; donor 5–35 year old male; donor 6–52 year old male; donor 7–50 year old female; donor 8–48 year old female; donor 9–53 year old female; donor 10–23 year old female.…”

Section: Methodsmentioning

confidence: 99%

The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma

Kumar

Tripolitsioti

et al. 2015

SpringerPlus

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Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-015-0784-2) contains supplementary material, which is available to authorized users.

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“…HD-MBO3 [17] was generously provided by Till Milde (DKFZ, Germany). DAOY cells were cultured as described in [33]. DAOY Lifeact-enhanced green fluorescent protein LA-EGFP cells were produced by lentiviral transduction of DAOY cells with pLenti-LA-EGFP.…”

Section: Cells and Cell Culturementioning

confidence: 99%

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

Neve

Migliavacca

Capdeville

et al. 2019

Cancers

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In the Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB), tumor initiation and progression are in part driven by smoothened (SMO) and fibroblast growth factor (FGF)-receptor (FGFR) signaling, respectively. We investigated the impact of the SMO-FGFR crosstalk on tumor growth and invasiveness in MB. We found that FGFR signaling represses GLI1 expression downstream of activated SMO in the SHH MB line DAOY and induces MKI67, HES1, and BMI1 in DAOY and in the group 3 MB line HD-MBO3. FGFR repression of GLI1 does not affect proliferation or viability, whereas inhibition of FGFR is necessary to release SMO-driven invasiveness. Conversely, SMO activation represses FGFR-driven sustained activation of nuclear ERK. Parallel activation of FGFR and SMO in ex vivo tumor cell-cerebellum slice co-cultures reduced invasion of tumor cells without affecting proliferation. In contrast, treatment of the cells with the SMO antagonist Sonidegib (LDE225) blocked invasion and proliferation in cerebellar slices. Thus, sustained, low-level SMO activation is necessary for proliferation and tissue invasion, whereas acute, pronounced activation of SMO can repress FGFR-driven invasiveness. This suggests that the tumor cell response is dependent on the relative local abundance of the two factors and indicates a paradigm of microenvironmental control of invasion in SHH MB through mutual control of SHH and FGFR signaling.

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NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma

Cited by 33 publications

References 46 publications

miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1

miR-140-5p inhibits human glioma cell growth and invasion by targeting JAG1

The Ser/Thr kinase MAP4K4 drives c-Met-induced motility and invasiveness in a cell-based model of SHH medulloblastoma

Crosstalk between SHH and FGFR Signaling Pathways Controls Tissue Invasion in Medulloblastoma

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