Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling
Copyright © 2023 Elsevier GmbH. All rights reserved..
BACKGROUND: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored.
METHODS: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts.
RESULTS: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment.
CONCLUSION: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:126 |
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| Enthalten in: |
Phytomedicine : international journal of phytotherapy and phytopharmacology - 126(2024) vom: 29. März, Seite 155208 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jia, Wentao [VerfasserIn] |
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| Links: |
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| Themen: |
6SMK8R7TGJ |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.phymed.2023.155208 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368772632 |
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| 100 | 1 | |a Jia, Wentao |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling |
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| 500 | |a Date Revised 11.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier GmbH. All rights reserved. | ||
| 520 | |a BACKGROUND: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored | ||
| 520 | |a METHODS: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts | ||
| 520 | |a RESULTS: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment | ||
| 520 | |a CONCLUSION: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a Hypoxia | |
| 650 | 4 | |a Oleanolic acid | |
| 650 | 4 | |a Premetastatic niche | |
| 650 | 4 | |a Tumor-derived exosomes | |
| 650 | 7 | |a Oleanolic Acid |2 NLM | |
| 650 | 7 | |a 6SMK8R7TGJ |2 NLM | |
| 650 | 7 | |a NF-kappa B |2 NLM | |
| 700 | 1 | |a Liang, Shufang |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Mingming |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Jiaying |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jinbo |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Wanfu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yuqian |e verfasserin |4 aut | |
| 700 | 1 | |a Nie, Shuchang |e verfasserin |4 aut | |
| 700 | 1 | |a Ling, Changquan |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Binbin |e verfasserin |4 aut | |
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