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

• Published in: Genes & development 2014-11, Vol.28 (22), p.2532-2546
• Main Authors: Zhang, Liang, Ge, Yejing, Fuchs, Elaine
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - metabolism; Animals; ATPases Associated with Diverse Cellular Activities; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - physiopathology; Cell Differentiation - genetics; Cell Survival - genetics; Cell Transformation, Neoplastic - genetics; Disease Progression; Endosomal Sorting Complexes Required for Transport - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Keratinocytes - cytology; Keratinocytes - pathology; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; Mitogen-Activated Protein Kinases - metabolism; Research Paper; Signal Transduction; Skin Neoplasms - genetics; Skin Neoplasms - physiopathology; Transcriptome
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.248377.114

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.