Hypoxia regulates sumoylation pathways in intervertebral disc cells: implications for hypoxic adaptations

Wang, Fei; Cai, Feng; Shi, Ruixia; Wei, Ji-Nan

doi:10.1016/j.joca.2016.01.134

Cited by 21 publications

(21 citation statements)

References 48 publications

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“…Previous study showed that NP cells tolerated oxygen deficiency and regulated the sumoylation pathways to improve cell survival in the hypoxic IVD. 24 The viability of NP cells showed no significant loss under hypoxia. In addition to cell viability, hypoxia also modulates cell metabolism, motility, autophagy, erythropoiesis, angiogenesis, and even inflammatory response.…”

Section: Discussionmentioning

confidence: 93%

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The influence of oxygen concentration on the extracellular matrix production of human nucleus pulposus cells during isolation‐expansion process

Yang

et al. 2017

J Biomedical Materials Res

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Nucleus pulposus (NP) cells locate in the center of avascular intervertebral discs, and thus have presumably adapted to a hypoxic environment. The purpose of this study was to investigate the influences of hypoxic condition, during isolation-expansion of human NP cells, on the cellular proliferation and extracellular matrix (ECM) synthesis in later three-dimensional cultures. Human NP tissues were obtained from patients who underwent lumbar disc surgeries. Immediately after retrieval, NP tissues from each patient were divided into two aliquots for in vitro cultivation either under classical normoxic (21% O ) or hypoxic (3.5% O ) condition. After isolation-expansion processes, microtissues of NP cells were formed and the analysis was performed after one-week culture. Experiments of pretreatment with TGF-β1 or lovastatin were designed to investigate if the isolation-expansion conditions affect the responsiveness to later exogenous treatments. Hypoxic isolation-expansion stimulated NP cell proliferation during monolayer culture. Hypoxia also upregulated mRNA levels of SOX9 and HIF-1α but downregulated type X collagen as well as improved aggrecan and type II collagen synthesis. Although TGF-β1 had no substantial effect, lovastatin pretreatment showed a greater enhancement on type II collagen expression in hypoxic group. Normoxia negatively affected the biochemical composition of regenerated ECM attributable to downregulation of SOX9 and HIF-1α, while hypoxia enhanced cellular proliferation, improved matrix production, and maintained a functional phenotype of NP cells. Hypoxic isolation-expansion of human NP cells is important to achieve better regenerative cells for later cultivation or cell transplantation. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1575-1582, 2017.

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Section: Discussionmentioning

confidence: 93%

“…All NP cells showed a chondrogenic phenotype under both oxygen partial pressures, and cells had similar viability. Previous study showed that NP cells tolerated oxygen deficiency and regulated the sumoylation pathways to improve cell survival in the hypoxic IVD . The viability of NP cells showed no significant loss under hypoxia.…”

Section: Discussionmentioning

confidence: 95%

The influence of oxygen concentration on the extracellular matrix production of human nucleus pulposus cells during isolation‐expansion process

Yang

et al. 2017

J Biomedical Materials Res

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“…SUMOylation is involved in the regulation of apoptosis-associated signaling pathways, such as p53, death-associated protein (Daxx) and dynamin-related protein 1 (Drp1) (21)(22)(23). As a member of the SUMOs superfamily, SUMO2 is crucial for the degradation and apoptosis of NPCs through the activation of p53 signaling pathway (24,25). Based on our nding that SUMO2 was a direct target of miR-25 in human NPCs, we speculate that miR-25 controlled the growth of NPCs in IDD via SUMO2.…”

Section: Discussionmentioning

confidence: 99%

MiR-25 Protects Against Apoptosis of Nucleus Pulposus Cells by Targeting SUMO2 in Intervertebral Disc Degeneration

Lei

Li²,

Guang³

et al. 2020

Preprint

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Background MiR-25 was reported to be down-regulated in patients with intervertebral disc degeneration (IDD). However, the potential role of miR-25 in IDD remained unclear. Therefore, the present study aimed to investigate the effects of miR-25 on human intervertebral disc nucleus pulposus cells (NPCs).Methods We evaluated the expression of miR-25 and small ubiquitin-related modifier 2 (SUMO2) in human nucleus pulposus (NP) tissues by real-time PCR and western blotting. Then, the target relationship between miR-25 and SUMO2 was validated by luciferase reporter assay and biotin-coupled miRNA pulldown assay. The potential roles of miR-25 in NPC proliferation and apoptosis were confirmed using CCK-8 assay, EdU incorporation assay, and flow cytometry.Results MiR-25 was lowly expressed in the patients with IDD. In addition, miR-25 facilitated the growth of NPCs by increasing cell proliferation and inhibiting apoptosis. Furthermore, we elucidated that SUMO2 was a target gene of miR-25, and was regulated by miR-25 through p53 signaling pathway. Restore of SUMO2 expression abrogated the effects of miR-25 on NPCs.Conclusion MiR-25 promoted the proliferation, inhibited the apoptosis of NPCs, and suppressed the development of IDD via SUMO2-mediated p53 signaling axis.

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“…degradation of HIF-1α (8). However, SUMO-1, which has a similar structure to that of ubiquitin, competes with ubiquitin for HIF-1α and thus protects HIF-1α from degradation (22). Previous studies have demonstrated that RWDD3 is able to enhance the stabilization and transcriptional activity of HIF-1α during hypoxia via promoting the sumoylation of HIF-1α, through which RWDD3 may serve a promoting role in tumor growth and metastasis (8,10).…”

Section: Discussionmentioning

confidence: 99%

Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3‑kinase/protein kinase B signaling

et al. 2018

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Glioblastoma is the most common and malignant primary brain tumor. RWD domain containing 3 (RWDD3) has been previously reported to serve a promoting role in pituitary tumors. However, the exact role of RWDD3 in glioblastoma remains unclear. Therefore, the present study aimed to investigate the expression levels of RWDD3 in human glioblastoma tissues and cell lines, as well as to examine the regulatory mechanism of RWDD3 underlying glioblastoma growth and metastasis. The results revealed that RWDD3 was significantly upregulated in glioblastoma tissues compared with normal brain tissues, while high expression of RWDD3 was associated with a shorter survival time of glioblastoma patients. The expression levels of RWDD3 were also higher in the glioblastoma cell lines compared with the normal human astrocyte cell line. Subsequent to knockdown of RWDD3, the proliferation of glioblastoma U87 and U251 cells was significantly decreased, possibly due to the cell cycle arrest at G1 phase, as well as the increased cell apoptosis. Furthermore, downregulation of RWDD3 also suppressed U87 and U251 cell invasion by inhibiting the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9. Molecular mechanism investigation demonstrated that knockdown of RWDD3 significantly downregulated the activity of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Activation of PI3K/AKT signaling prevented the suppressive effects of RWDD3 downregulation on glioblastoma cell proliferation and migration, concurrent with increased protein levels of MMP2 and MMP9. In conclusion, the current study demonstrated for the first time that inhibition of RWDD3 expression inhibited glioblastoma progression, at least partly, via suppressing the PI3K/AKT signaling activity, and thus RWDD3 may be a novel potential therapeutic target for glioblastoma.

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Hypoxia regulates sumoylation pathways in intervertebral disc cells: implications for hypoxic adaptations

Abstract: NP and AF cells equally tolerate oxygen deficiency, but differently regulate the sumoylation pathways under hypoxia. The distinct sumoylation dynamics may help extend our understanding of the cell-specific regulation of the molecular basis that promotes cell survival in the hypoxic IVD.

Cited by 21 publications

References 48 publications

The influence of oxygen concentration on the extracellular matrix production of human nucleus pulposus cells during isolation‐expansion process

The influence of oxygen concentration on the extracellular matrix production of human nucleus pulposus cells during isolation‐expansion process

MiR-25 Protects Against Apoptosis of Nucleus Pulposus Cells by Targeting SUMO2 in Intervertebral Disc Degeneration

Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3‑kinase/protein kinase B signaling

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