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Title: The Role of microRNAs in Fibroblast Quiescence and Extracellular Matrix Synthesis
Authors: Suh, Eric Jungwoo
Advisors: Coller, Hilary A
Contributors: Molecular Biology Department
Keywords: Cancer
Cell cycle
Extracellular matrix
Subjects: Molecular biology
Cellular biology
Issue Date: 2013
Publisher: Princeton, NJ : Princeton University
Abstract: Although quiescence&ndash;reversible cell-cycle arrest&ndash;is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. I sought to clarify the role of microRNAs as regulators of the cellular functions of quiescence using a neonatal human dermal fibroblast culture model. Using microarrays, I discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, I discovered a strong regulatory function for <italic>miR-29</italic>, which is downregulated with quiescence. Using microarrays and immunoblotting, I confirmed that <italic>miR-29</italic> targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of <italic>miR-29</italic> resulted in more rapid cell cycle re-entry from quiescence. microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts. Building upon the work on <italic>miR-29</italic> in quiescence, I investigated the role of fibroblasts and the connection between anti-mitogenic stimulus and extracellular matrix formation in the tumor microenvironment, focusing on the desmoplastic reaction in breast cancer. I developed a TGF-&beta; and <italic>miR-29</italic> signature using microarray data sets in fibroblasts, and I then used these signatures to reanalyze public clinical breast cancer data sets. I confirmed that high TGF-&beta; signaling exists in tumor stroma, which is consistent with the literature, but I also found that this signaling seemed to anticorrelate slightly with the repressive activities of <italic>miR-29</italic>. Finally, I began preliminary experiments towards establishing an <italic>in vitro</italic> model of tumor-fibroblast interactions to investigate the role of <italic>miR-29</italic> in tumor-stroma interactions.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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