Retinoic acid receptor‐related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia

Li, Hongyu; Zhou, Longjian; Dai, Jun

doi:10.1002/jcp.25924

Cited by 21 publications

(18 citation statements)

References 46 publications

(81 reference statements)

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“…The results obtained in this study are in line with previous studies, which demonstrated an altered expression of several barrier proteins including FLG, LOR and INV under hypoxia, indicative for a restructured barrier formation 33,35 . Furthermore, silencing of HIF-α affected the terminal differentiation program in a human epidermal model that resulted in impaired stratification of the epidermis 32 .…”

Section: Discussionsupporting

confidence: 92%

Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation

Mieremet

García

Boiten

et al. 2019

Sci Rep

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Human skin equivalents (HSEs) are three-dimensional cell models mimicking characteristics of native human skin (NHS) in many aspects. However, a limitation of HSEs is the altered in vitro morphogenesis and barrier formation. Differences between in vitro and in vivo skin could have been induced by suboptimal cell culture conditions, of which the level of oxygen in vitro (20%) is much higher than in vivo (0.5–8%). Our aim is to study how external oxygen levels affect epidermal morphogenesis and barrier formation in HSEs. In the present study, fibroblast and keratinocyte monocultures, and HSEs were generated under 20% (normoxia) and 3% (hypoxia) oxygen level. In all cultures under hypoxia, expression of hypoxia-inducible factor target genes was increased. Characterization of HSEs generated under hypoxia using immunohistochemical analyses of morphogenesis biomarkers revealed a reduction in epidermal thickness, reduced proliferation, similar early differentiation, and an attenuated terminal differentiation program compared to normoxia, better mimicking NHS. The stratum corneum ceramide composition was studied with liquid chromatography coupled to mass spectrometry. Under hypoxia, HSEs exhibited a ceramide composition that more closely resembles that of NHS. Consequently, the lipid organization was improved. In conclusion, epidermal morphogenesis and barrier formation in HSEs reconstructed under hypoxia better mimics that of NHS.

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Section: Discussionsupporting

confidence: 92%

Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation

Mieremet

García

Boiten

et al. 2019

Sci Rep

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“…Recent studies have shown that hypoxia induces RORα expression and that RORα expression protects keratinocytes, attenuates apoptotic potential via caspase 3/7‐related pathway and promotes its survival under hypoxic conditions . Furthermore, decreased expression of RORα was followed by attenuation of HIF1α‐regulated expression of genes related to cell differentiation, such as involucrin, prolyl hydroxylase‐3, adipose differentiation‐related protein and others .…”

Section: Discussionmentioning

confidence: 99%

“…Other studies showed that the expression of RORα increased in variety of cells under hypoxic conditions that is mediated by the interaction of HIF‐1α to an HRE in the promoter region of RORα . On the other hand, RORα enhances HIF‐1α protein stability, its nuclear localization, transactivation functions and HIF‐1α transcriptional activity . In addition, HIF1‐α, acting via transcriptional activation of RORγt, promotes the development of Th17 cells …”

Section: Introductionmentioning

confidence: 99%

“…In osteoclasts, vitamin D analogs, acting via VDR, can regulate HIF‐1α expression . Other studies showed that the expression of RORα increased in variety of cells under hypoxic conditions that is mediated by the interaction of HIF‐1α to an HRE in the promoter region of RORα . On the other hand, RORα enhances HIF‐1α protein stability, its nuclear localization, transactivation functions and HIF‐1α transcriptional activity .…”

Section: Introductionmentioning

confidence: 99%

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On the relationship between VDR, RORα and RORγ receptors expression and HIF1‐α levels in human melanomas

Brożyna

Jóźwicki

Jetten

et al. 2019

Experimental Dermatology

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We analysed the correlation between the expression of HIF‐1α (hypoxia‐inducible factor 1 alpha), the nuclear receptors: VDR (vitamin D receptor), RORα (retinoic acid receptor‐related orphan receptor alpha), and RORγ and CYP24A1 (cytochrome P450 family 24 subfamily A member 1) and CYP27B1 (cytochrome P450 family 27 subfamily B member 1), enzymes involved in vitamin D metabolism. In primary and metastatic melanomas, VDR negatively correlated with nuclear HIF‐1α expression (r = −.2273, P = .0302; r = −.5081, P = .0011). Furthermore, the highest HIF‐1α expression was observed in pT3‐pT4 VDR‐negative melanomas. A comparative analysis of immunostained HIF‐1α and CYP27B1 and CYP24A1 showed lack of correlation between these parameters both in primary tumors and melanoma metastases. In contrast, RORα expression correlated positively with nuclear HIF‐1α expression in primary and metastatic lesions (r = .2438, P = .0175; r = .3662, P = .0166). Comparable levels of HIF‐1α expression pattern was observed in localized and advanced melanomas. RORγ in primary melanomas correlated also positively with nuclear HIF‐1α expression (r = .2743, P = .0129). HIF‐1α expression was the lowest in localized RORγ‐negative melanomas. In addition, HIF‐1α expression correlated with RORγ‐positive lymphocytes in melanoma metastases. We further found that in metastatic lymph nodes FoxP3 immunostaining correlated positively with HIF‐1α and RORγ expression in melanoma cells (r = .3667; P = .0327; r = .4208, P = .0129). In summary, our study indicates that the expression of VDR, RORα and RORγ in melanomas is related to hypoxia and/or HIF1‐α activity, which also affects FoxP3 expression in metastatic melanoma. Therefore, the hypoxia can affect tumor biology by changing nuclear receptors expression and molecular pathways regulated by nuclear receptors and immune responses.

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“…The ephrin-A3 gene (efna3) is shown as a key functional mediator of hypoxic microenvironment and is regarded as a therapeutic target for hypoxia-specific disease [39]. Retinoic acid receptor-related orphan receptor alpha (rora) was demonstrated to be an important mediator of HIF-1α activities in human [40]. Finally, the aurora kinase A (aurka) gene, a serine kinase in neuroblastoma that stimulate cell growth or migration, can up-regulate expression in human BE(2)-C cells under hypoxia [41].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Association Analysis of Adaptation to Oxygen Stress in Nile Tilapia (Oreochromis Niloticus)

Megens

Mengistu

et al. 2020

Preprint

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Background: Tilapia is one of the most abundant species in aquaculture. Hypoxia is known to depress growth rate, but the genetic mechanism by which this occurs is unknown. In this study, two groups consisting of 3140 fish that were raised in either aerated (normoxia) or non-aerated pond (nocturnal hypoxia). During grow out, fish were sampled five times to determine individual body weight (BW) gains. We applied a genome-wide association study to identify SNPs and genes associated with the hypoxic and normoxic environments in the 17th generation of a Genetically Improved Farmed tilapia population. Results: In the hypoxic environment, 36 SNPs associated with at least one of the five body weight measurements (BW1 till BW5), of which six, located between 19.48 Mb and 21.04 Mb on Linkage group (LG) 8, were significant for body weight in the early growth stage (BW1 to BW2). Further significant associations were found for BW in the later growth stage (BW3 to BW5), located on LG1 and LG8. Analysis of genes within the candidate genomic region suggested that MAPK and VEGF signalling were significantly involved in the later growth stage under the hypoxic environment. Well-known hypoxia-regulated genes such as igf1rb, rora, efna3 and aurk were also associated with growth in the later stage in the hypoxic environment. Conversely, 13 linkage groups containing 29 unique significant and suggestive SNPs were found across the whole growth period under the normoxic environment. A meta-analysis showed that 33 SNPs were significantly associated with BW across the two environments, indicating a shared effect independent of hypoxic or normoxic environment. Functional pathways involved in nervous system development and organ growth in the early stage, and oocyte maturation in the later stage.Conclusions: There are clear genotype-growth associations in both normoxic and hypoxic environments, although genome architecture involved changed over the growing period, indicating a transition in metabolism along the way. The involvement of pathways important in hypoxia especially at the later growth stage indicates a genotype-by-environment interaction, in which MAPK and VEGF signalling are important components.

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Retinoic acid receptor‐related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia

Cited by 21 publications

References 46 publications

Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation

Human skin equivalents cultured under hypoxia display enhanced epidermal morphogenesis and lipid barrier formation

On the relationship between VDR, RORα and RORγ receptors expression and HIF1‐α levels in human melanomas

Genome-wide Association Analysis of Adaptation to Oxygen Stress in Nile Tilapia (Oreochromis Niloticus)

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