A microRNA signature and TGF-β1 response were identified as the key master regulators for spaceflight response

Beheshti, Afshin; Ray, Shayoni; Fogle, Homer; Berrios, Daniel C.; Costes, Sylvain V.

doi:10.1371/journal.pone.0199621

Cited by 35 publications

(57 citation statements)

References 56 publications

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“…Other oncogenic trends we observed were decreases in CSR, ESC, TGFβ, VEGFA, and mTOR C6 pathway levels as a function of increasing radiation dose (Figures 7 and 8). TGFβ, VEGFa, and mTOR have all previously shown similar trends with increasing dose of simulated space radiation [32,88]. The ESC C6 term is refers to differentiation of embryonic stem cells (ESC) [89].…”

Section: Discussionmentioning

confidence: 83%

“…In addition, we found specific cancer-related pathways that may be unique to space radiation. For example, decreases in TGFβ [32], embryonic stem cells (ESC) [95], and VEGFa seem to be unique to space radiation. Spaceflight studies have previously revealed a plethora of effects that radiation can have at individual doses or over a small range of discreet doses.…”

Section: Discussionmentioning

confidence: 99%

“…There was a total of 25 GeneLab datasets (GLDS) with 30 experimental comparisons from RNA-sequencing or microarray platforms (Table 1). Data pre-processing was performed as previously published to obtain normalized expression values for the majority of the datasets [32,33,42]. For GLDS-73, human bronchial epithelial cells (HBECs) were exposed to gamma-rays (1 Gy or 3 Gy), iron ( 56 Fe), or silicon ( 26 Si) particles (0.5 Gy or 1 Gy each).…”

Section: Bioinformatics Gene Set Enrichment Analysis and Visulizatimentioning

confidence: 99%

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NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

McDonald¹,

Stainforth

Cahill

et al. 2020

Cancers

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Background: Ionizing radiation from galactic cosmic rays (GCR) is one of the major risk factors that will impact the health of astronauts on extended missions outside the protective effects of the Earth’s magnetic field. The NASA GeneLab project has detailed information on radiation exposure using animal models with curated dosimetry information for spaceflight experiments. Methods: We analyzed multiple GeneLab omics datasets associated with both ground-based and spaceflight radiation studies that included in vivo and in vitro approaches. A range of ions from protons to iron particles with doses from 0.1 to 1.0 Gy for ground studies, as well as samples flown in low Earth orbit (LEO) with total doses of 1.0 mGy to 30 mGy, were utilized. Results: From this analysis, we were able to identify distinct biological signatures associating specific ions with specific biological responses due to radiation exposure in space. For example, we discovered changes in mitochondrial function, ribosomal assembly, and immune pathways as a function of dose. Conclusions: We provided a summary of how the GeneLab’s rich database of omics experiments with animal models can be used to generate novel hypotheses to better understand human health risks from GCR exposures.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Bioinformatics Gene Set Enrichment Analysis and Visulizatimentioning

confidence: 99%

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NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

McDonald¹,

Stainforth

Cahill

et al. 2020

Cancers

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“…Gene set enrichment analysis showed a highly significant association between the overrepresented miRNAs and nonsmall cell lung and other cancers, consistent with the idea that exosomal miRNA could influence the risk of cancer development at the tissue level. Interestingly, four of the over-represented RNAs, are also part of a miRNA signature identified as a master regulator for spaceflight response, based on computational analysis of the NASA GeneLab database (Beheshti et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Characterization of exosome release and extracellular vesicle-associated miRNAs for human bronchial epithelial cells irradiated with high charge and energy ions

Dynan

Jaafar

et al. 2020

Preprint

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Exosomes are extracellular vesicles that mediate transport of nucleic acids, proteins, and other molecules. Prior work has implicated exosomes in the transmission of radiation nontargeted effects. Here we investigate the ability of energetic heavy ions, representative of species found in galactic cosmic rays, to stimulate exosome release from human bronchial epithelial cells in vitro. Immortalized human bronchial epithelial cells (HBEC3-KT F25F) were irradiated with 1.0 Gy of high linear energy transfer (LET) 48Ti, 28Si, or 16O ions, or with 10 Gy of low-LET reference γ-rays, and extracellular vesicles were collected from conditioned media. Preparations were characterized by single particle tracking analysis, transmission electron microscopy, and immunoblotting for the exosomal marker, TSG101. Irradiation with high-LET ions, but not γ-rays, stimulated exosome release by about 3-fold, relative to mock-irradiated controls. The exosome-enriched vesicle preparations contained pro-inflammatory damage-associated molecular patterns, including HSP70 and calreticulin. Additionally, miRNA profiling was performed for vesicular RNAs using NanoString technology. The miRNA profile was skewed toward a small number of species that have previously been shown to be involved in cancer initiation and progression, including miR-1246, miR-1290, miR-23a, and miR-205. Additionally, a set of 24 miRNAs was defined as modestly over-represented in preparations from HZE ion-irradiated versus other cells. Gene set enrichment analysis based on the over-represented miRNAs showed highly significant association with nonsmall cell lung and other cancers.

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“…Hinz [74] suggested that the TGF-β complex functions as an extracellular mechanosensory that can be activated by contractile forces that are transmitted by integrins. Indeed, µg was identified as a possible cause changing TGF-β expression levels [75]. In four-hour cultures stacked on the RPM, the TGFB1 mRNA was slightly elevated whereas in three-day cultures the mRNA level was attenuated, maybe due to missing forces in µg.…”

Section: Cell Detachment In Microgravity and Epithelial-mesenchymal Tmentioning

confidence: 99%

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity

Melnik

Sahana

Corydon

et al. 2020

Cells

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Detachment and the formation of spheroids under microgravity conditions can be observed with various types of intrinsically adherent human cells. In particular, for cancer cells this process mimics metastasis and may provide insights into cancer biology and progression that can be used to identify new drug/target combinations for future therapies. By using the synthetic glucocorticoid dexamethasone (DEX), we were able to suppress spheroid formation in a culture of follicular thyroid cancer (FTC)-133 cells that were exposed to altered gravity conditions on a random positioning machine. DEX inhibited the growth of three-dimensional cell aggregates in a dose-dependent manner. In the first approach, we analyzed the expression of several factors that are known to be involved in key processes of cancer progression such as autocrine signaling, proliferation, epithelial–mesenchymal transition, and anoikis. Wnt/β-catenin signaling and expression patterns of important genes in cancer cell growth and survival, which were further suggested to play a role in three-dimensional aggregation, such as NFKB2, VEGFA, CTGF, CAV1, BCL2(L1), or SNAI1, were clearly affected by DEX. Our data suggest the presence of a more complex regulation network of tumor spheroid formation involving additional signal pathways or individual key players that are also influenced by DEX.

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A microRNA signature and TGF-β1 response were identified as the key master regulators for spaceflight response

Cited by 35 publications

References 56 publications

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

NASA GeneLab Platform Utilized for Biological Response to Space Radiation in Animal Models

Characterization of exosome release and extracellular vesicle-associated miRNAs for human bronchial epithelial cells irradiated with high charge and energy ions

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity

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