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TRANSCRIPTIONAL AND POST TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION: APPLICATIONS TO BIOLOGY AND CANCER

Elgamal, Ola A
http://orcid.org/0000-0001-5011-3909
http://rave.ohiolink.edu/etdc/view?acc_num=osu1461071345

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Pharmacy.
miRNA dysregulation in cancer has been reported in numerous studies suggesting an important role for these small noncoding RNAs in cancer initiation or progression. In this study, we report the consequences of miR-205 and miR-217 dysregulation in breast cancer and in pancreatic acinar to ductal metaplasia, respectively. While reduction of miR-205 was previously reported in breast cancer, we confirmed reduced expression of miR-205 in triple negative breast cancer (TNBC) and identified a novel miR-205 target, HMGB3. The loss of miR-205 correlated with the upregulation of HMGB3 in patient specimens of breast cancer. Furthermore, patients with increased HMGB3 protein has poor survival compared to patients with low levels of HMGB3. siRNA knockdown of HMGB3 in TNBC cell lines reduced in vitro tumor cell proliferation and invasion. In summary, we report the tumor suppressive role for miR-205 is due in part to targeting HMGB3. Acinar to ductal metaplasia (ADM) is an early event in pancreatic cancer where acinar cells lose their identity and transdifferentiate into ductal-like cells. In the presence of inflammation and mutations, two common risk factors for pancreatic cancer, ADM progresses into pancreatic intraepithelial neoplasia (PanIN) lesions, which further advances into pancreatic ductal adenocarcinoma (PDAC). Using a three dimensional in vitro culture of primary mouse acinar cells, we evaluated the molecular dysregulation of miRNAs during ADM. Previously we have shown that miR-217 targets the transcriptional repressor REST/NRSF and during experimental ADM, miR-217 is reduced and REST/NRSF increases. In this dissertation, we confirmed REST regulation by miR-217 and studied the consequences of enforced expression of Rest on ADM. Using adenoviral vectors, we report that Rest promoted duct formation, increased ductal markers, and reduced several key acinar markers. Collectively, our data suggests an ADM promoting role for Rest and we hypothesize that miR-217 loss mediates the upregulation of REST during ADM. We propose a feedforward mechanism of regulation where miR-217 loss during ADM de-represses REST which in turn, silences acinar promoting transcription factors. Our data suggest that de-repressing miR-205 or miR-217 in tumors, treating tumors with miRNA mimics or silencing the target genes of these miRNAs are promising therapeutic options. One approach to treat cancer with miRNA mimics or other oligonucleotides is to use a targeted nanoparticle approach. Recently, extracellular vesicles (EVs) have gained great interest for their potential as drug delivery vehicles. Here, we introduce a method to scale-up the production of HEK293T-derived EVs and evaluate their cellular uptake and in vitro safety in monocytic cell lines. The in vitro data provided herein should be beneficial to others who are proposing in vivo studies of therapeutic EVs.
Mitchell Phelps (Advisor)
Thomas Schmittgen (Committee Member)
207 p.
Pharmaceuticals; Pharmacy Sciences

Recommended Citations

Citations

  • Elgamal, O. A. (2016). TRANSCRIPTIONAL AND POST TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION: APPLICATIONS TO BIOLOGY AND CANCER [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461071345

    APA Style (7th edition)

  • Elgamal, Ola. TRANSCRIPTIONAL AND POST TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION: APPLICATIONS TO BIOLOGY AND CANCER. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1461071345.

    MLA Style (8th edition)

  • Elgamal, Ola. "TRANSCRIPTIONAL AND POST TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION: APPLICATIONS TO BIOLOGY AND CANCER." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461071345

    Chicago Manual of Style (17th edition)

osu1461071345
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This open access ETD is published by The Ohio State University and OhioLINK.