EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis
© 2017 Sundaram et al..
Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal-regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2017 |
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Erschienen: |
2017 |
Enthalten in: |
Zur Gesamtaufnahme - volume:214 |
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Enthalten in: |
The Journal of experimental medicine - 214(2017), 10 vom: 02. Okt., Seite 2889-2900 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Sundaram, Gopinath M [VerfasserIn] |
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Links: |
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Themen: |
62229-50-9 |
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Anmerkungen: |
Date Completed 24.10.2017 Date Revised 13.11.2018 published: Print-Electronic RefSeq: NM_003685, NM_005219 Citation Status MEDLINE |
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doi: |
10.1084/jem.20170354 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM275004988 |
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100 | 1 | |a Sundaram, Gopinath M |e verfasserin |4 aut | |
245 | 1 | 0 | |a EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis |
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520 | |a © 2017 Sundaram et al. | ||
520 | |a Epithelial carcinomas are well known to activate a prolonged wound-healing program that promotes malignant transformation. Wound closure requires the activation of keratinocyte migration via a dual-state molecular switch. This switch involves production of either the anti-migratory microRNA miR-198 or the pro-migratory follistatin-like 1 (FSTL1) protein from a single transcript; miR-198 expression in healthy skin is down-regulated in favor of FSTL1 upon wounding, which enhances keratinocyte migration and promotes re-epithelialization. Here, we reveal a defective molecular switch in head and neck squamous cell carcinoma (HNSCC). This defect shuts off miR-198 expression in favor of sustained FSTL1 translation, driving metastasis through dual parallel pathways involving DIAPH1 and FSTL1. DIAPH1, a miR-198 target, enhances directional migration through sequestration of Arpin, a competitive inhibitor of Arp2/3 complex. FSTL1 blocks Wnt7a-mediated repression of extracellular signal-regulated kinase phosphorylation, enabling production of MMP9, which degrades the extracellular matrix and facilitates metastasis. The prognostic significance of the FSTL1-DIAPH1 gene pair makes it an attractive target for therapeutic intervention | ||
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700 | 1 | |a Kuznetsov, Vladimir |e verfasserin |4 aut | |
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700 | 1 | |a Sampath, Prabha |e verfasserin |4 aut | |
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