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

Knarr, Matthew J
http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
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.
Analisa DiFeo, PhD (Advisor)
Ruth Keri, PhD (Committee Chair)
Mark Jackson, PhD (Committee Member)
Johannes Von Lintig, PhD (Committee Member)
Jason Mears, PhD (Committee Member)
382 p.
Biomedical Research
miRNA; ovarian cancer; oncogenic transformation

Recommended Citations

Citations

  • Knarr, M. J. (2019). The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007

    APA Style (7th edition)

  • Knarr, Matthew. The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007.

    MLA Style (8th edition)

  • Knarr, Matthew. "The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007

    Chicago Manual of Style (17th edition)

case1554481048956007
48
© 2019, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.