Although specific microRNAs (miRNAs) can be upregulated in cancer, global miRNA downregulation is a common trait of human malignancies. The mechanisms of this phenomenon and the advantages it affords remain poorly understood. Here we identify a microRNA family, miR-103/107, that attenuates miRNA biosynthesis by targeting Dicer, a key component of the miRNA processing machinery. In human breast cancer, high levels of miR-103/107 are associated with metastasis and poor outcome. Functionally, miR-103/107 confer migratory capacities in vitro and empower metastatic dissemination of otherwise nonaggressive cells in vivo. Inhibition of miR-103/107 opposes migration and metastasis of malignant cells. At the cellular level, a key event fostered by miR-103/107 is induction of epithelial-to-mesenchymal transition (EMT), attained by downregulating miR-200 levels. These findings suggest a new pathway by which Dicer inhibition drifts epithelial cancer toward a less-differentiated, mesenchymal fate to foster metastasis.

The two first cell fate decisions taken in the mammalian embryo generate three distinct cell lineages: one embryonic, the epiblast, and two extraembryonic, the trophoblast and primitive endoderm. miRNAs are essential for early development, but it is not known if they are utilized in the same way in these three lineages. We find that in the pluripotent epiblast they inhibit apoptosis by blocking the expression of the proapoptotic protein Bcl2l11 (Bim) but play little role in the initiation of gastrulation. In contrast, in the trophectoderm, miRNAs maintain the trophoblast stem cell compartment by directly inhibiting expression of Cdkn1a (p21) and Cdkn1c (p57), and in the primitive endoderm, they prevent differentiation by maintaining ERK1/2 phosphorylation through blocking the expression of Mapk inhibitors. Therefore, we show that there are fundamental differences in how stem cells maintain their developmental potential in embryonic and extraembryonic tissues through miRNAs.

Background: X chromosome inactivation is the mechanism used in mammals to achieve dosage compensation of X-linked genes in XX females relative to XY males. Chromosome silencing is triggered in cis by expression of the non-coding RNA Xist. As such, correct regulation of the Xist gene promoter is required to establish appropriate X chromosome activity both in males and females. Studies to date have demonstrated co-transcription of an antisense RNA Tsix and low-level sense transcription prior to onset of X inactivation. The balance of sense and antisense RNA is important in determining the probability that a given Xist allele will be expressed, termed the X inactivation choice, when X inactivation commences.