MicroRNA-146a and Ets-1 Gene Polymorphisms Are Associated with Pediatric Uveitis

Lin, Wei; Zhou, Qingyun; Hou, Shengping; Bai, Lin; Liu, Yunjia; Qi, Jian; Qin, Xiang; Zhou, Yan; Kijlstra, Aize; Yang, Peizeng

doi:10.1371/journal.pone.0091199

Cited by 30 publications

(22 citation statements)

References 32 publications

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“…Other regulators have also been described, such as NF-kB (43), V-Ets oncogene homolog 1 (ETS1; ref. 44), as well as epigenetics (45) and feedback (43) mechanisms. Autoregulation could also occur during melanoma progression; this would make the scenario even more complex if one considers miR-146a for therapeutic interventions in melanoma.…”

Section: Discussionmentioning

confidence: 99%

miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization

Raimo

Orso

Grassi

et al. 2016

Molecular Cancer Research

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Malignant melanoma is the most aggressive form of skin cancer; therefore, it is crucial to disclose its underlying molecular mechanisms. MicroRNAs (miRNAs) are small endogenous noncoding RNAs able to posttranscriptionally downregulate the expression of direct target genes. Using a melanoma progression model, miR-146a was identified as a key double-acting player in melanoma malignancy. In fact, miR-146a is able to enhance tumor growth, while it suppresses dissemination. It was determined that miR-146a coordinated melanoma cell growth by its direct targets lunatic fringe (LFNG) and NUMB, which operate on the NOTCH/PTEN/Akt pathway; while inhibition of metastasis formation was linked to decreased expression of ITGAV and ROCK1. Relevantly, miR-146a expression correlated with melanoma recurrence and was enriched in both patient-derived melanoma and cutaneous metastasis specimens, while its direct targets were depleted. However, miR-146a levels drop in circulating tumor cells (CTCs), suggesting the necessity for miR-146a expression to fluctuate during tumor progression in order to favor tumor growth and allow dissemination. This study reconciles the contradictory biologic functions of miR-146a in melanoma progression and unravels distinct molecular mechanisms that need to be considered for therapeutic interventions.

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Section: Discussionmentioning

confidence: 99%

miR-146a Exerts Differential Effects on Melanoma Growth and Metastatization

Raimo

Orso

Grassi

et al. 2016

Molecular Cancer Research

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“…Loss of the Ets1 gene in mice leads to increased B cell differentiation into IgM and IgG secreting plasma cells and high titers of autoantibodies against common self-antigens such as DNA, histones, and IgG (28, 29). Polymorphisms in the human ETS1 gene are also linked with autoimmune and inflammatory diseases, including systemic lupus erythematosus (SLE) (30–35), rheumatoid arthritis (36, 37), psoriasis (38), ankylosing spondylitis (39), uveitis (40) and celiac disease (41). It is possible that these polymorphisms lead to lower c-ets-1 expression.…”

Section: Introductionmentioning

confidence: 99%

Requirement for Transcription FactorEts1in B Cell Tolerance to Self-Antigens

Russell

John

Cullen

et al. 2015

The Journal of Immunology

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The differentiation and survival of autoreactive B cells is normally limited by a variety of self-tolerance mechanisms including clonal deletion, anergy and clonal ignorance. The transcription factor c-ets-1 (encoded by the Ets1 gene) has B cell-intrinsic roles in regulating formation of antibody-secreting cells (ASCs) by controlling the activity of Blimp1 and Pax5 and may be required for B cell tolerance to self-antigen. To test this, we crossed Ets1−/− mice to two different transgenic models of B cell self-reactivity, the anti-hen egg lysozyme BCR transgenic strain and the AM14 rheumatoid factor transgenic strain. BCR transgenic Ets1−/− mice were subsequently crossed to mice either carrying or lacking relevant autoantigens. We found that B cells lacking c-ets-1 are generally hyper-responsive in terms of antibody secretion and form large numbers of ASCs even in the absence of cognate antigens. When in the presence of cognate antigen, different responses were noted depending on the physical characteristics of the antigen. We found that clonal deletion of highly autoreactive B cells in the bone marrow was intact in the absence of c-ets1. However, peripheral B cells lacking c-ets-1 failed to become tolerant in response to stimuli that normally induce B cell anergy or B cell clonal ignorance. Interestingly, high affinity soluble self-antigen did cause B cells to adopt many of the classical features of anergic B cells, although such cells still secreted antibody. Therefore, maintenance of appropriate c-ets-1 levels is essential to prevent loss of self-tolerance in the B cell compartment.

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“…Intriguingly, rs4937362 locates at approximately 35 kb upstream of ETS1, which plays an important role in autoimmune diseases, such as SLE, psoriasis, RA, MS, pediatric uveitis, and hematopoietic tumors. 65,66 These findings suggest that RP11-264E20.1 rs4937362 possibility affects disease susceptibility by regulating ETS1. It is not clear why rs4937362 associated with AS þ AAU À but not in AS patients with AAU.…”

Section: Discussionmentioning

confidence: 80%