Dataset Information

Loss of miR-155 upregulates WEE1 in metastatic melanoma.

ABSTRACT: Significant advances have been made in the treatment of melanoma by targeting key cellular pathways, but additional targets are needed as many patients do not respond or relapse with resistant disease. MicroRNA-155 (MiR-155) has previously been shown to regulate melanoma cell growth and acts as a tumor suppressor. We tested a clinical population of melanoma tumors for miR-155 expression, and find that expression is low in most patients, although not predictive of outcome. We identified the protein kinase WEE1 as a novel target of miR-155. A mouse model of experimental metastasis finds that both increased expression of miR-155 and silencing of WEE1 lead to decreased metastases. Loss of miR-155 and increased expression of WEE1 may contribute to the metastatic phenotype in patients with melanoma.

SUBMITTER: DiSano JA

PROVIDER: S-EPMC8522211 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Loss of miR-155 upregulates WEE1 in metastatic melanoma.

DiSano Julie A JA Huffnagle Ian I Gowda Raghavendra R Spiegelman Vladimir S VS Robertson Gavin P GP Pameijer Colette R CR

Melanoma research 20190401 2

Significant advances have been made in the treatment of melanoma by targeting key cellular pathways, but additional targets are needed as many patients do not respond or relapse with resistant disease. MicroRNA-155 (MiR-155) has previously been shown to regulate melanoma cell growth and acts as a tumor suppressor. We tested a clinical population of melanoma tumors for miR-155 expression, and find that expression is low in most patients, although not predictive of outcome. We identified the prote ...[more]

PMID: 30499870

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Project description:MicroRNA (miR) miR-155 modulates microglial activation and polarization, but its role in activation of microglia during bacterial brain infection is unclear. We studied miR-155 expression in brains of C57BL/6 (B6.WT) mice infected i.p. with the neuro-invasive bacterial pathogen Listeria monocytogenes (L. monocytogenes). Infected mice were treated with ampicillin starting 2 days (d) post-infection (p.i.) and analyzed 3d, 7d, and 14d p.i. Virulent L. monocytogenes strains EGD and 10403s upregulated miR-155 in whole brain 7 d p.i. whereas infection with avirulent, non-neurotropic Δhly or ΔactA L. monocytogenes mutants did not. Similarly, infection with virulent but not mutated bacteria upregulated IFN-γ mRNA in the brain at 7 d p.i. Upregulation of miR-155 in microglia was confirmed by qPCR of flow cytometry-sorted CD45intCD11bpos brain cells. Subsequently, brain leukocyte influxes and gene expression in sorted microglia were compared in L. monocytogenes-infected B6.WT and B6.Cg-Mir155tm1.1Rsky/J (B6.miR-155-/-) mice. Brain influxes of Ly-6Chigh monocytes and upregulation of IFN-related genes in microglia were similar to B6.WT mice at 3 d p.i. In contrast, by d 7 p.i. expressions of microglial IFN-related genes, including markers of M1 polarization, were significantly lower in B6.miR-155-/- mice and by 14 d p.i., influxes of activated T-lymphocytes were markedly reduced. Notably, CD45highCD11bpos brain cells from B6.miR-155-/- mice isolated at 7 d p.i. expressed 2-fold fewer IFN-γ transcripts than did cells from B6.WT mice suggesting reduced IFN-γ stimulation contributed to dampened gene expression in B6.miR-155-/- microglia. Lastly, in vitro stimulation of 7 d p.i. brain cells with heat-killed L. monocytogenes induced greater production of TNF in B6.miR-155-/- microglia than in B6.WT microglia. Thus, miR-155 affects brain inflammation by multiple mechanisms during neuroinvasive L. monocytogenes infection. Peripheral miR-155 promotes brain inflammation through its required role in optimal development of IFN-γ-secreting lymphocytes that enter the brain and activate microglia. Microglial miR-155 promotes M1 polarization, and also inhibits inflammatory responses to stimulation by heat-killed L. monocytogenes, perhaps by targeting Tab2.

Dataset Information

Loss of miR-155 upregulates WEE1 in metastatic melanoma.

Publications

Loss of miR-155 upregulates WEE1 in metastatic melanoma.

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