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

作者：Gopinath Meenakshi Sundaram, Hisyam M. Ismail, Mohsin Bashir, Manish Muhuri, Candida Vaz, Srikanth Nama, Ghim Siong Ow, Ivshina Anna Vladimirovna, Rajkumar Ramalingam, Brian E. Burke, Vivek Tanavde, Vladimir A. Kuznetsov, Ellen Birgitte Lane, Prabha Sampath · 发表于：The Journal of Experimental Medicine · 年份：2017 · DOI：10.1084/jem.20170354 · 被引用次数：77 · 研究领域：RNA Research and Splicing、Connective tissue disorders research、Kruppel-like factors research

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.