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Previously, we identified  miR-125b  as a key regulator of the undifferentiated state of hair follicle stem cells. Here, we show that in both mice and humans,  miR-125b  is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma (SCC), the second most prevalent cancer worldwide. Moreover, when elevated in normal murine epidermis,  miR-125b  promotes tumor initiation and contributes to malignant progression. We further show that  miR-125b  can confer “oncomiR addiction” in early stage malignant progenitors by delaying their differentiation and favoring an SCC cancer stem cell (CSC)-like transcriptional program. To understand how, we systematically identified and validated  miR125b  targets that are specifically associated with tumors that are dependent on  miR-125b . Through molecular and genetic analysis of these targets, we uncovered new insights underlying  miR-125b ’s oncogenic function. Specifically, we show that, on the one hand,  mir-125b  directly represses stress-responsive  MAP kinase  genes and associated signaling. On the other hand, it indirectly prolongs activated (phosphorylated) EGFR signaling by repressing  Vps4b  (vacuolar protein-sorting 4 homolog B), encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR. Together, these findings illuminate  miR-125b  as an important microRNA regulator that is shared between normal skin progenitors and their early malignant counterparts.

miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival