A Unique Regulation Region in the 3′ UTR of HLA-G with a Promising Potential

Reches, Adi; Berhani, Orit; Mandelboim, Ofer

doi:10.3390/ijms21030900

Cited by 13 publications

(11 citation statements)

References 32 publications

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“…The high tissue tropism of HLA-G is not only related to its unique promoter region but also its distinctive 3ʹUTR. 71 For example, inverse correlation between miR-628-5 p and HLA-G expression has been identified in renal cell carcinoma. 72 Upregulation of some miRNAs has also been reported to affect classical HLA-I expression by silencing HLA or components of APM.…”

Section: Transcriptional Silencingmentioning

confidence: 99%

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Hazini

Fisher

Seymour

2021

J Immunother Cancer

105

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It is now well accepted that many tumors undergo a process of clonal selection which means that tumor antigens arising at various stages of tumor progression are likely to be represented in just a subset of tumor cells. This process is thought to be driven by constant immunosurveillance which applies selective pressure by eliminating tumor cells expressing antigens that are recognized by T cells. It is becoming increasingly clear that the same selective pressure may also select for tumor cells that evade immune detection by acquiring deficiencies in their human leucocyte antigen (HLA) presentation pathways, allowing important tumor antigens to persist within cells undetected by the immune system. Deficiencies in antigen presentation pathway can arise by a variety of mechanisms, including genetic and epigenetic changes, and functional antigen presentation is a hard phenomenon to assess using our standard analytical techniques. Nevertheless, it is likely to have profound clinical significance and could well define whether an individual patient will respond to a particular type of therapy or not. In this review we consider the mechanisms by which HLA function may be lost in clinical disease, we assess the implications for current immunotherapy approaches using checkpoint inhibitors and examine the prognostic impact of HLA loss demonstrated in clinical trials so far. Finally, we propose strategies that might be explored for possible patient stratification.

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Section: Transcriptional Silencingmentioning

confidence: 99%

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Hazini

Fisher

Seymour

2021

J Immunother Cancer

105

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“…The unidentified responsive elements for IL-10 and glucocorticoids are under-identified in the HLA-G promoter. There are also a variety of single nucleotide polymorphism (SNPs) in 3' untranslated region (UTR) of HLA-G that influence mRNA stability, turnover and mobility, including +3035C/T, +3187A/G, +3196C/G, +3142C/G, +3001C/T, +3003C/T, +3010C/G, +3027C/A, +3032C/G, +3052C/T, +3092G/T, +3111A/G, +3121C/T, +3177G/T, +3183A/G, and +3227A/G (14,15). These SNPs alter the binding of microRNA (miR), leading to decreased expression of HLA-G. Six types of miRs have been identified, namely; miR148a, miR148b, miR152, miR133a, miR628-5p, and miR548q.…”

Section: Structure Alternative Splicing Variants and Translated Isoforms Of Hla-gmentioning

confidence: 99%

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

2021

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Maternal-fetal immune-tolerance occurs throughout the whole gestational trimester, thus a mother can accept a genetically distinct fetus without immunological aggressive behavior. HLA-G, one of the non-classical HLA class I molecules, is restricted-expression at extravillous trophoblast. It can concordantly interact with various kinds of receptors mounted on maternally immune cells residing in the uterus (e.g. CD4+ T cells, CD8+ T cells, natural killer cells, macrophages, and dendritic cells) for maintaining immune homeostasis of the maternal-fetus interface. HLA-G is widely regarded as the pivotal protective factor for successful pregnancies. In the past 20 years, researches associated with HLA-G have been continually published. Indeed, HLA-G plays a mysterious role in the mechanism of maternal-fetal immune-tolerance. It can also be ectopically expressed on tumor cells, infected sites and other pathologic microenvironments to confer a significant local tolerance. Understanding the characteristics of HLA-G in immunologic tolerance is not only beneficial for pathological pregnancy, but also helpful to the therapy of other immune-related diseases, such as organ transplant rejection, tumor migration, and autoimmune disease. In this review, we describe the biological properties of HLA-G, then summarize our understanding of the mechanisms of fetomaternal immunologic tolerance and the difference from transplant tolerance. Furthermore, we will discuss how HLA-G contributes to the tolerogenic microenvironment during pregnancy. Finally, we hope to find some new aspects of HLA-G in fundamental research or clinical application for the future.

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“…An additional layer of posttranscriptional regulation of HLA-G protein expression is mediated by a specific RNA-binding protein (RBP) ( Figure 1 ), the heterogeneous nuclear ribonucleoprotein R (HNRNPR), which binds the 3′ UTR of the transcripts, stabilizes them, and allows HLA-G1 expression in transduced cell lines ( 61 ). More recently, a distinct and unique region in the 3′ UTR of HLA-G has been identified, but neither miRNAs nor RBPs seem to bind to this site and to control HLA-G1 expression in cell lines ( 62 ). Thus, additional studies are warranted to define the relevance of this sequence into the regulation of HLA-G protein expression in vivo .…”

Section: Intracellular and Extracellular Mechanisms Regulating Hla-g mentioning

confidence: 99%

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

Amodio

Gregori

2020

Front. Immunol.

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The non-classical HLA-G is a well-known immune-modulatory molecule. In physiological condition, HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues, whereas soluble forms of HLA-G are detectable in various body fluids. HLA-G can be de novo expressed in pathological conditions including tumors, chronic infections, or after allogeneic transplantation. HLA-G exerts positive effects modulating innate and adaptive immune responses and promoting tolerance, or detrimental effects inducing immune escape mechanisms. HLA-G locus, in contrast to classical HLA class I gene, is highly polymorphic in the non-coding 3 ′ untranslated region (UTR) and in the 5 ′ upstream regulatory region (5 ′ URR). Variability in these regions influences HLA-G expression by modifying mRNA stability or allowing posttranscriptional regulation in the case of 3 ′ UTR or by sensing the microenvironment and responding to specific stimuli in the case of HLA-G promoter regions (5 ′ URR). The influence of genetic variations on the expression of HLA-G makes it an attractive biomarker to monitor disease predisposition and progression, or response to therapy. Here, we summarize the current knowledge, efforts, and obstacles to generate a general consensus on the correlation between HLA-G genetic variability, protein expression, and disease predisposition. Moreover, we discuss perspectives for future investigation on HLA-G genotype/expression in association with disease predisposition and progression.

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A Unique Regulation Region in the 3′ UTR of HLA-G with a Promising Potential

Cited by 13 publications

References 32 publications

Deregulation of HLA-I in cancer and its central importance for immunotherapy

Deregulation of HLA-I in cancer and its central importance for immunotherapy

HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance

HLA-G Genotype/Expression/Disease Association Studies: Success, Hurdles, and Perspectives

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