EGF hijacks miR-198/FSTL1 wound-healing switch and steers a two-pronged pathway toward metastasis

GM Sundaram, HM Ismail, M Bashir, M Muhuri… - Journal of Experimental …, 2017 - rupress.org
GM Sundaram, HM Ismail, M Bashir, M Muhuri, C Vaz, S Nama, GS Ow, IA Vladimirovna…
Journal of Experimental Medicine, 2017rupress.org
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 …
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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