The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation

Bibliographic Details
Main Author:	Knarr, Matthew J.
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2019
Subjects:	Biomedical Research miRNA ovarian cancer oncogenic transformation
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case15544810489560072021-08-03T07:10:08Z The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation Knarr, Matthew J. Biomedical Research miRNA ovarian cancer oncogenic transformation MiRNAs are important regulators of diverse cellular processes including proliferation, apoptosis, and differentiation. In the context of bone marrow derived stromal cell and adipose derived stromal cell differentiation, miRNAs are established regulators of both differentiation or stemness depending on their target. Furthermore, miRNA dysregulation can play a key role in various disease states. Here we show that miR-181a is regulated in a circadian manner and is induced during immortalized bone marrow derived stromal cell (iBMSC) adipogenesis. Enhanced expression of miR-181a in iBMSCs as well as primary patient adipose derived stromal cells (ASCs) produced a robust increase in adipogenesis through the direct targeting of the circadian factor Period circadian clock 3 (PER3). Taken together, our data identify a previously unknown functional link between miR-181a and the circadian machinery in immortalized bone marrow stromal cells and adipose derived stromal cells highlighting its importance in iBMSC and ASC adipogenesis and circadian biology. Genomic instability is known to predispose cells to malignant transformation, highlighting the need to understand how it is maintained in a cell. The molecular mechanisms that allow for the propagation of cell populations with a high-degree of genomic instability and nuclear defects remain unclear. Here we report that miR-181a is able to transform HGSOC precursor cells. Using HGSOC precursor cells, we show that a miR-181a driven program promotes oncogenic transformation by targeting the tumor suppressor retinoblastoma (RB1) resulting in anchorage independent growth, nuclear atypia, persistent nuclear rupture, and genomic instability. In turn, the propagation of these genomically unstable cells is dependent on the inhibition of STING, a key-signaling molecule that activates interferon signaling to prevent genomic instability and tumorigenesis as well as activate anti-tumor immunity. Collectively, our findings elucidate a novel oncogenic function of miR-181a in the creation of both a cellular context conducive to the maintenance of cells with profound genomic instability and the promotion of tumorigenesis. Using miR-181a as an archetype, our results illuminate a poorly characterized stage of HGSOC ontogeny by showing that oncogenic alterations that can initiate punctuated genomic instability while also inhibiting signaling that prevents genomic instability and tumorigenesis are prime candidates to facilitate the oncogenic transitions. 2019-05-23 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007 http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Biomedical Research miRNA ovarian cancer oncogenic transformation
spellingShingle	Biomedical Research miRNA ovarian cancer oncogenic transformation Knarr, Matthew J. The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
author	Knarr, Matthew J.
author_facet	Knarr, Matthew J.
author_sort	Knarr, Matthew J.
title	The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
title_short	The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
title_full	The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
title_fullStr	The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
title_full_unstemmed	The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation
title_sort	monkey in the wrench: mir-181a's role in promoting adipogenesis and ovarian cancer transformation
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2019
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007
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The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation

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