4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate

Kuroda, Yoshiyuki; Kasai, Kosuke; Nanashima, Naoki; Nozaka, Hiroyuki; Nakano, Manabu; Chiba, Mitsuru; Yoneda, Masahiko; Nakamura, Toshiya

doi:10.2220/biomedres.34.97

Cited by 10 publications

(7 citation statements)

References 37 publications

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“…An enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of HA in medium as described previously 9 56 57 . Culture media was collected after treatment and 96-well plates were precoated with HABC (a hyaluronan-binding complex).…”

Section: Methodsmentioning

confidence: 99%

Conserved miR-26b enhances ovarian granulosa cell apoptosis through HAS2-HA-CD44-Caspase-3 pathway by targeting HAS2

Liu

Wang

et al. 2016

Sci Rep

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The hyaluronan synthase 2 (HAS2)-hyaluronic acid (HA)-CD44-Caspase-3 pathway is involved in ovarian granulosa cell (GC) functions in mammals. HAS2 is a key enzyme required for HA synthesis and is the key factor in this pathway. However, the regulation of HAS2 and the HAS2-mediated pathway by microRNAs in GCs is poorly understood. Here, we report that miR-26b regulates porcine GC (pGC) apoptosis through the HAS2-HA-CD44-Caspase-3 pathway by binding directly to the 3′- untranslated region of HAS2 mRNA. Knockdown of miR-26b reduced pGC apoptosis. Luciferase reporter assays demonstrated that HAS2 is a direct target of miR-26b in pGCs. Knockdown and overexpression of miR-26b increased and decreased, respectively, HA content, and HAS2 and CD44 expression in pGCs. At the same time, inhibition and overexpression of miR-26b decreased and increased the expression of Caspase-3, a downstream factor in the HAS2-HA-CD44 pathway. Moreover, knockdown of HAS2 enhanced pGC apoptosis, reduced the inhibitory effects of a miR-26b inhibitor on pGC apoptosis, repressed HA content and CD44 expression, and promoted Caspase-3 expression. In addition, overexpression of HAS2 has a opposite effect. Collectively, miR-26b positively regulates pGC apoptosis via a novel HAS2-HA-CD44-Caspase-3 pathway by targeting the HAS2 gene.

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Section: Methodsmentioning

confidence: 99%

Conserved miR-26b enhances ovarian granulosa cell apoptosis through HAS2-HA-CD44-Caspase-3 pathway by targeting HAS2

Liu

Wang

et al. 2016

Sci Rep

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“…4-Methylumbelliferone (4-MU) is a hyaluronan synthesis inhibitor (13,14) that has demonstrated anti-tumor and -invasion/metastasis effects in various cancer cell types and mouse models of prostate and liver cancer that are exerted via suppression of hyaluronan synthase (HAS) expression (15,16). 4-MU was also shown to suppress inflammatory cytokines and chemokines such as interleukin (IL)-6 and -8 (17).…”

Section: Introductionmentioning

confidence: 99%

Regulation of radiosensitivity by 4‑methylumbelliferone via the suppression of interleukin‑1 in fibrosarcoma cells

et al. 2019

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Tumor recurrence and distant metastasis following radiotherapy, which can lead to poor prognosis, are caused by residual cancer cells that acquire radioresistance. Chemotherapy or a combination of targeted inhibitors can potentially enhance radiation sensitivity and prevent metastasis. It was previously reported that co-administration of the hyaluronan synthesis inhibitor 4-methylumbelliferone (4-MU) enhanced the lethality of X-ray irradiation in HT1080 human fibrosarcoma cells and decreased their invasiveness to a greater extent than either treatment alone. To clarify the molecular basis of these effects, the present study conducted mRNA expression profiling by cDNA microarray to identify the signaling pathways that are altered under this combination treatment. The activation state of the signaling pathways was classified by z-scores in the Ingenuity Pathway Analysis. The results revealed that the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 were activated by 2 Gy X-ray irradiation, an effect that was abolished by co-administration of 4-MU. Similar trends were observed for the upstream signaling component IL-1. These results indicate that the radiosensitivity of fibrosarcoma cells is improved by suppressing inflammation through the administration of 4-MU.

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“…As HAS2 is a multi-pass membrane-bound enzyme [46], the regulation of p27-SKP2-CDK2 pathway by HAS2 is likely an indirect effect. HAS2 may interact with other cytoplasmic proteins [47], such as protein kinase C (PKC) [48] to influence down-stream signaling mediating cellular senescence. Furthermore, HAS2-mediated senescence may be through CD44-HA interactions.…”

Section: Discussionmentioning

confidence: 99%

Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis

Liang

Yang

et al. 2016

Matrix Biology

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Dysregulated repair of lung injury often results in lung fibrosis characterized by unremitting deposition of matrix components including the glycosaminoglycan hyaluronan (HA). HA is mainly produced by hyaluronan synthases (HAS) in mesenchymal cells. We previously demonstrated that over-expression of HAS2 in mesenchymal cells in mice regulates the invasiveness of fibroblasts and promotes severe lung fibrosis. The mechanisms that control the resolution of lung fibrosis are unknown. We propose that a critical step in resolving fibrosis is the induction of senescence in fibrotic fibroblasts and hyaluronan synthase 2 may regulate this process. We found that fibrotic fibroblasts developed the characteristics of replicative senescence in culture and that HAS2 expression was dramatically down-regulated. Furthermore, down-regulation of HAS2 initiated and regulated fibroblast senescence through a p27-CDK2-SKP2 pathway. Deletion of HAS2 in mouse mesenchymal cells increased the cellular senescence of fibroblasts in bleomycin-induced mouse lung fibrosis in vivo. These data suggest that HAS2 may be a critical regulator of the fate of pulmonary fibrosis and we propose a model where over-expression of HAS2 promotes an invasive phenotype resulting in severe fibrosis and down-regulation of HAS2 promotes resolution. Targeting HAS2 to induce fibroblast senescence could be an attractive approach to resolve tissue fibrosis.

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4-Methylumbelliferone inhibits the phosphorylation of hyaluronan synthase 2 induced by 12-O-tetradecanoyl-phorbol-13-acetate

Cited by 10 publications

References 37 publications

Conserved miR-26b enhances ovarian granulosa cell apoptosis through HAS2-HA-CD44-Caspase-3 pathway by targeting HAS2

Conserved miR-26b enhances ovarian granulosa cell apoptosis through HAS2-HA-CD44-Caspase-3 pathway by targeting HAS2

Regulation of radiosensitivity by 4‑methylumbelliferone via the suppression of interleukin‑1 in fibrosarcoma cells

Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis

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