Hypoxia Modulates HLA-G Gene Expression in Tumor Cells

Mouillot, Gaël; Marcou, Céline; Zidi, Inès; Guillard, Christine; Sangrouber, Déborah; Carosella, Edgardo D.; Moreau, Philippe

doi:10.1016/j.humimm.2006.10.016

Cited by 104 publications

(99 citation statements)

References 43 publications

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“…Altered expressions of HLA-I and HLA-E molecules by parental and RCC-pE cells, and the results of blocking experiments, suggest that VHL is responsible for the susceptibility of these cells to NK-mediated lysis. The previously reported expression of HLA-G by RCC6 (Ibrahim et al, 2001) is decreased by transfection with the wild-type VHL gene, in agreement with the link between HIF-1 stabilization and HLA-G expression by melanoma cells (Mouillot et al, 2007) and trophoblast (Kilburn et al, 2000). Transfection with the wild-type VHL had no effect on the expression of ligands for NKG2D and DNAM-1 activating NK receptors.…”

Section: Discussionsupporting

confidence: 77%

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

et al. 2011

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The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-a results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cellmediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1a and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNc secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-Ispecific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNa, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNa resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with antiangiogenic drugs may be beneficial for patients with mutated VHL.

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Section: Discussionsupporting

confidence: 77%

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

et al. 2011

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“…22 Furthermore, hypoxia has been demonstrated to differentially affect HLA-G expression in various tumor cell lines by inducing HLA-G gene transcription in some HLA-G Ϫ lines and decreasing constitutive expression in certain HLA-G ϩ lines, indicating that modulation of HLA-G expression by hypoxic treatment is dependent on cell type. 18 Interestingly, the HLA-G promoter contains a heat shock element, which binds to heat shock factor 1, a transcriptional factor activated during conditions of environmental stress, providing more evidence that HLA-G expression might be stress-inducible. 23 We therefore assessed the effect of H/R in our vascular and smooth muscle cell cultures, but did not detect HLA-G expression after injury.…”

Section: Discussionmentioning

confidence: 99%

“…Signaling molecules such as progesterone, 14,15 interferon-␥, 16 and interleukin-10, 17 which are present at high levels during gestation, are capable of enhancing HLA-G expression. Interventions associated with transplantation such as hypoxic injury 18 and immunosuppressive therapy 9 might also regulate this expression. Additionally, genetic factors are known to modulate HLA-G gene expression, because HLA-G allelic differences are associated with differential HLA-G mRNA levels and isoform profiles.…”

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confidence: 99%

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

et al. 2008

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Background-Human leukocyte antigen-G (HLA-G) expression in heart transplant patients has been negatively associated with acute cellular rejection and cardiac allograft vasculopathy. We assessed HLA-G expression in vascular human endothelial and smooth muscle cell cultures to determine if future therapeutic agents can be targeted toward inducing HLA-G expression to protect against allograft rejection and vasculopathy. Methods and Results-Human coronary artery endothelial, aortic endothelial, and coronary artery smooth muscle cell cultures were exposed to cytokines (interferon-␥ or interleukin-10), hypoxia/reoxygenation stress, immunosuppressive agents (cyclosporine, sirolimus, or tacrolimus), or progesterone. HLA-G was not expressed by untreated, normoxic cells. Furthermore, maximal doses of interferon-␥, interleukin-10, cyclosporine, sirolimus, or tacrolimus, as well as exposure to hypoxia/reoxygenation, failed to induce HLA-G expression. HLA-G, which has previously not been detected in adult vascular endothelial and smooth muscle cells, was detected by enzyme-linked immunosorbent assay and flow cytometry in human coronary artery endothelial, human coronary aortic endothelial, and human coronary artery smooth muscle cultures after incubation with progesterone in a dose-dependent manner (PϽ0.001) with no change in cellular proliferation ability or viability. This effect was partially blocked in the presence of mifepristone, a progesterone receptor antagonist (human coronary artery endothelial: 48.8Ϯ15.6%; human coronary aortic endothelial: 59.5Ϯ9.5%; human coronary artery smooth muscle: 59.8Ϯ9.8% of control; PϽ0.05). Progesterone-induced HLA-G expression was not protective against hypoxia/reoxygenation injury. Conclusions-HLA-G is not expressed at baseline in vascular endothelial and smooth muscle cells but can be induced by exposure to progesterone. Although tightly regulated, induction of HLA-G expression in these cells may represent a promising and novel therapeutic strategy to protect against rejection and cardiac allograft vasculopathy after heart transplantation.

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“…A few HLA-G promoter binding factors and their target sites have been characterized such as CREB1 (28), IFN regulatory factor 1 (35), heat shock transcription factor 1 (36), or progesterone receptor (37). Microenvironmental parameters have been shown to play a key role in the modulation of HLA-G gene, including stress conditions such as heat shock (36) or hypoxia (38), cytokines such as IFN (35,39), IL-10 (40), leukemia inhibitory factor (41), GM-CSF (42), and hormones such as glucocorticoids (43) or progesterone (44). However, for most of them the mechanism of action remains unknown.…”

Section: Rreb-1 Is a Transcriptionalmentioning

confidence: 99%

RREB-1 Is a Transcriptional Repressor of HLA-G

Flajollet

Poras

Carosella

et al. 2009

The Journal of Immunology

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The nonclassical HLA-G is a molecule specifically involved in immune tolerance with highly restricted tissue distribution in healthy conditions. Yet it is overexpressed in numerous tumors and in allografts with better acceptance. Major mechanisms involved in regulation of HLA-G transcription are still poorly described. Thus, to characterize these mechanisms we have developed a specific proteomic approach to identify proteins that bind differentially to the HLA-G gene promoter by promoter pull-down assay followed by spectrometry mass analysis. Among specific binding factors, we focused on RREB-1, a ras-responsive element binding protein 1. We demonstrated that RREB-1 represses HLA-G transcriptional activity and binds three ras response elements within the HLA-G promoter. RREB-1 protein, specifically in HLA-G-negative cells, interacts with subunits of CtBP complex implicated in chromatin remodeling. This demonstration is the first of a repressor factor of HLA-G transcriptional activity taking part in HLA-G repression by epigenetic mechanisms.

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Hypoxia Modulates HLA-G Gene Expression in Tumor Cells

Cited by 104 publications

References 43 publications

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

Mutations of the von Hippel–Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma

Progesterone Induces Human Leukocyte Antigen-G Expression in Vascular Endothelial and Smooth Muscle Cells

RREB-1 Is a Transcriptional Repressor of HLA-G

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