miR-203, a microRNA of multilayered epithelia, inhibits metastatic fitness in human squamous cell carcinoma

The colonization of distant organs by metastatic carcinoma cells underpins most human cancer-related deaths, including those from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that promotes keratinocyte differentiation, is necessary and sufficient to inhibit multiple post-extravasation events during HNSCC lung metastasis, including initial survival/engraftment, escape from metastatic dormancy, and overt colonization in vivo. Restoration of miR-203 expression in established lung metastases reduces overall metastatic burden. Instead of promoting differentiation, miR-203 controls lung metastasis through direct targeting of genes involved in cytoskeletal dynamics (LASP1), ECM remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream targets correlates with HNSCC overall survival outcomes, suggesting the therapeutic potential of targeting this signaling axis. Total RNA (including small RNAs) was isolated from cultured cells stably infected in biological duplicate with either a scrambled control hairpin or miR-203. Samples were harvested in technical duplicate.