HLA-G 3′ untranslated region variants +3187G/G, +3196G/G and +3035T define diametrical clinical status and disease outcome in epithelial ovarian cancer

Schwich, Esther; Rebmann, Vera; Michita, Rafael Tomoya; Rohn, Hana; Voncken, Jan Willem; Horn, Peter A.; Kasimir‐Bauer, Sabine; Buderath, Paul

doi:10.1038/s41598-019-41900-z

Cited by 19 publications

(20 citation statements)

References 58 publications

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“…The 3 UTR of a given gene is an important regulatory site harboring many regulatory elements that control its post-transcription regulation [21]. The 3 UTR of HLA-G was reported to be bound by miR-148a, miR-148b, miR-152, miR-133a, miR-628-5p, and miR-548q, all leading to downregulation of HLA-G protein expression [23]. All of them bind sites that are also present in the 3 UTR of classical HLA class I proteins because although HLA-G has a different expression pattern, its 3 UTR is similar to the 3 UTRs of the classical HLA class I proteins.…”

Section: Discussionmentioning

confidence: 99%

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

Reches

Berhani

Mandelboim

2020

IJMS

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Human leukocyte antigen G (HLA-G) is a non-classical human leukocyte antigen (HLA) class I protein that interacts with inhibitory receptors and is commonly overexpressed in various cancers, thereby establishing itself as an inhibitory checkpoint immune ligand. It is also expressed in trophoblast cells during pregnancy and protects the fetus from immune rejection. Despite its crucial role and its intriguing expression pattern, the regulation of HLA-G’s expression is only partially understood. HLA-G’s mRNA is expressed in many tissues but the protein expression is restricted only to the cells mentioned above. Therefore, we suggest that HLA-G is post-transcriptionally regulated. Here, we reveal a distinctive site present only in the 3′ Untranslated region (UTR) of HLA-G, which might explain its unique expression pattern. Consequently, we attempted to find binding factors such as RNA binding proteins (RBPs) and microRNAS (miRs) that regulate HLA-G expression by interacting with this distinct site present in its 3′ UTR. Our research indicates that this site should be further studied in order to reveal its significance.

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Section: Discussionmentioning

confidence: 99%

“…Six miRs were already reported to regulate HLA-G expression by binding its 3' UTR: miR-148a, miR-148b, miR-152, miR-133a, miR-628-5p, and miR-548q [23]. However, not one of these miRs target HLA-G specifically, but rather also target other members of the HLA class I family.…”

Section: Introductionmentioning

confidence: 99%

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

Reches

Berhani

Mandelboim

2020

IJMS

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“…HLA-G can bind to a variety of receptors, such as CD8, leukocyte immunoglobulin-like receptor subfamily B member 1 (LIR-1), and killer cell immunoglobulin-like receptor (KIR), all of which protect cancer cells from CD8 T cell-or NK cell-induced killing (Wiendl et al 2002;Kochan et al 2013;Loumagne et al 2014;Lin and Yan 2015). HLA-G polymorphisms also impact graft-versus-tumor responses in renal cell carcinoma (Crocchiolo et al 2018) and correlate with outcome in epithelial ovarian carcinoma (Schwich et al 2019).…”

Section: Adhesion To the Endotheliummentioning

confidence: 99%

The Immune Microenvironment and Cancer Metastasis

El-Kenawi

Hänggi

Ruffell

2019

Cold Spring Harb Perspect Med

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The dynamic interplay between neoplastic cells and the immune microenvironment regulates every step of the metastatic process. Immune cells contribute to invasion by secreting a cornucopia of inflammatory factors that promote epithelial-to-mesenchymal transition and remodeling of the stroma. Cancer cells then intravasate to the circulatory system assisted by macrophages and use several pathways to avoid recognition by cytotoxtic lymphocytes and phagocytes. Circulating tumor cells that manage to adhere to the vasculature and encounter premetastic niches are able to use the associated myeloid cells to extravasate into ectopic organs and establish a dormant microscopic colony. If successful at avoiding repetitive immune attack, dormant cells can subsequently grow into overt, clinically detectable metastatic lesions, which ultimately account to most cancer-related deaths. Understanding how disseminated tumor cells evade and corrupt the immune system during the final stages of metastasis will be pivotal in developing new therapeutic modalities that combat metastasis.

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“…HLA-G gene displays low polymorphism but several mature mRNAs can be produced as a result of differential splicing of the primary transcript. The mature mRNAs encode 7 different protein isoforms, 4 of them being membrane-bound (HLA-G1 to G4), and 3 soluble or secreted (HLA-G5 to G7) [11]. Also, Roux et al reported an inventory of novel HLA-G isoforms that have an extended 5′-region and lack the transmembrane and alpha-1 domains [12].…”

Section: Introductionmentioning

confidence: 99%

“…Interaction of HLA-G with ILT2 requires the association of the α3 domain with β2M but not for binding to ILT4. The KIR2DL4 binds to the α1 domain [11,15,16].…”

Section: Introductionmentioning

confidence: 99%

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

et al. 2020

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Background: The Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms. Results: Out of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5′UTR. 5 SNPs in 3′UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers. Conclusions: The implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

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HLA-G 3′ untranslated region variants +3187G/G, +3196G/G and +3035T define diametrical clinical status and disease outcome in epithelial ovarian cancer

Cited by 19 publications

References 58 publications

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

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

The Immune Microenvironment and Cancer Metastasis

Predicting the most deleterious missense nsSNPs of the protein isoforms of the human HLA-G gene and in silico evaluation of their structural and functional consequences

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