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.

众所周知，上皮癌会激活延长的伤口愈合程序，从而促进恶性转化。伤口闭合需要通过双态分子开关激活角质形成细胞迁移。这种转换涉及从单个转录本产生抗迁移性microRNA miR-198或促迁移性卵泡抑素样1（FSTL1）蛋白。受伤后，健康皮肤中的miR-198表达下调，从而有利于FSTL1，从而增强了角质形成细胞的迁移并促进了上皮再生。在这里，我们揭示了头颈部鳞状细胞癌（HNSCC）中的一个有缺陷的分子开关。该缺陷关闭了miR-198的表达，有利于持续的FSTL1翻译，从而通过涉及DIAPH1和FSTL1的双重平行途径驱动转移。DIAPH1，miR-198靶标，通过螯合竞争性Arp2 / 3复合物抑制剂Arpin增强定向迁移。FSTL1阻断Wnt7a介导的细胞外信号调节激酶磷酸化的抑制，从而使MMP9产生，从而降解细胞外基质并促进转移。FSTL1-DIAPH1基因对的预后意义使其成为治疗干预的有吸引力的靶标。