Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression

Abstract

Micro (mi)RNAs are emerging as important regulators of cellular differentiation, their importance underscored by the fact that they are often dysregulated during carcinogenesis. Two evolutionary conserved families, let-7 and miR-200, regulate key differentiation processes during development. Loss of let-7 in cancer results in reverse embryogenesis and dedifferentiation, and miR-200 has been identified as a powerful regulator of epithelial-to-mesenchymal transition (EMT). Recent findings have connected let-7 with stem cell maintenance and point at a connection between EMT and stem cell formation. A part of tumor progression can be viewed as a continuum of progressive dedifferentiation (EMT) with a cell at the endpoint that has stem cell-like properties. I propose that steps of this process are driven by specific changes in the expression of let-7 and miR-200 family members.

Figure 1

Expression of let-7 and miR-200 Is Regulated by Negative Feedback Loops. (A) Regulation of let-7 processing by the let-7 targets Lin28/Lin28B. (B) Regulation of miR-200 expression by the miR-200 targets ZEB1/ZEB2. For details see text.

Figure 2

Model to Illustrate how let-7 and miR-200 Could Each Contribute to Tumor Progression, One by Controlling let-7 Regulated Oncofetal Genes (LOGs) and the Other by Regulating EMT and Metastasis. Crosstalk exists between the pathways that regulate reverse embryogenesis and EMT. For details see text.

Figure 3

Deregulation of let-7 and miR-200 during carcinogenesis.