An elegant miRror: microRNAs in stem cells,developmental timing and cancer |
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Authors: | Rachael A Nimmo Frank J Slack |
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Institution: | (1) Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520, USA |
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Abstract: | MicroRNAs (miRNAs) were first discovered in genetic screens for regulators of developmental timing in the stem-cell-like seam
cell lineage in Caenorhabditis elegans. As members of the heterochronic pathway, the lin-4 and let-7 miRNAs are required in the seam cells for the correct progression of stage-specific events and to ensure that cell cycle
exit and terminal differentiation occur at the correct time. Other heterochronic genes such as lin-28 and lin-41 are direct targets of the lin-4 and let-7 miRNAs. Recent findings on the functions of the let-7 and lin-4/mir-125 miRNA families and lin-28 and lin-41 orthologs from a variety of organisms suggest that core elements of the heterochronic pathway are retained in mammalian stem
cells and development. In particular, these genes appear to form bistable switches via double-negative feedback loops in both
nematode and mammalian stem cell development, the functional relevance of which is finally becoming clear. let-7 inhibits stem cell self-renewal in both normal and cancer stem cells of the breast and acts as a tumor suppressor in lung
and breast cancer. let-7 also promotes terminal differentiation at the larval to adult transition in both nematode stem cells and fly wing imaginal
discs and inhibits proliferation of human lung and liver cancer cells. Conversely, LIN-28 is a highly specific embryonic stem
cell marker and is one of four “stemness” factors used to reprogram adult fibroblasts into induced pluripotent stem cells;
furthermore, lin-28 is oncogenic in hepatocellular carcinomas. Therefore, a core module of heterochronic genes—lin-28, lin-41, let-7, and lin-4/mir-125—acts as an ancient regulatory switch for differentiation in stem cells (and in some cancers), illustrating that nematode
seam cells mirror miRNA regulatory networks in mammalian stem cells during both normal development and cancer. |
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