Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population, as well as an economic load to the health care system; yet treatments of these preventable cancers remain ineffective.,Studies estimate that there has been a 2-fold increase in the incidence of NMSCs between the 1960s and 1980s.,The increase in cases of NMSCs, as well as the lack of effective treatments, makes the need for novel therapeutic approaches all the more necessary.,To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgently required.,Research over the past few years has provided data supporting both a “bottom up” and “top down” mechanism of tumourigenesis.,The “bottom up” concept involves a cancer stem cell originating in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers.,The “top down” concept involves a more differentiated cell undergoing genetic modifications leading to dedifferentiation, giving rise to cancer initiating cells (CICs).,This review explores both concepts, to paint a picture of the skin SCC cell of origin, the underlying biology, and also how this knowledge might be exploited to develop novel therapies.
Zhang et al. show that miR-125b is abundantly expressed, particularly at early stages of malignant progression to squamous cell carcinoma.,When elevated in normal murine epidermis, miR-125b promotes tumor initiation and contributes to malignant progression. mir-125b directly represses stress-responsive MAPK genes and indirectly prolongs activated EGFR signaling by repressing Vps4B, encoding a protein implicated in negatively regulating the endosomal sorting complexes that are necessary for the recycling of active EGFR.,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.