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Target Identification, Therapeutic Application and Maturation Mechanism of microRNAs

Park, Jong Kook
http://rave.ohiolink.edu/etdc/view?acc_num=osu1331096696

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Pharmacy.
Extensive profiling studies over the past several years have demonstrated that various miRNAs are differentially expressed in most cancers. Uncovering potential targets, and biogenesis regulation factors will be necessary for miRNA based cancer therapy in the future. We identified a novel target gene of miR-132 and miR-212 which are over-expressed in pancreatic adenocarcinoma (PDAC). Both miRNAs directly regulate the retinoblastoma tumor suppressor, Rb1, in pancreatic tumor cells. Cell proliferation was enhanced in panc-1 cells by ectopic expression of pre-miR-132/-212 oligos together with increased E2F target genes. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G2/M cell cycle arrest. Beta 2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression in panc-1 cells. Differentially expressed miRNAs in hepatocellular carcinoma (HCC) include miR-221 (up-regulated) and miR-199a-3p (down-regulated). Therapeutic efficacy of miR-221 antisense oligonucleotides and a tumor suppressive role of miR-199a-3p were evaluated in HCC. The cholesterol-modified anti-miR-221 (chol-anti-miR-221) had improved pharmacokinetics and liver tissue distribution compared to the non-cholesterol labeled oligonucleotide. Intravenously administered chol-anti-miR-221 accumulated in the tumors of orthotopic mouse models of HCC. Anti-miR-221 was effective at inhibiting endogenous miRNA and modulating target gene expression. Chol-anti-miR-221 produced a survival advantage in orthotopic mice compared to those mice treated with a scrambled control. To determine if miR-199a-3p has a tumor suppressive role, pre-miR-199a-3p oligonucleotides were transfected into the HCC cell lines. Pre-miR-199a-3p reduced cell proliferation by approximately 60% compared to control oligonucleotide in SNU449 and SNU423 cells. Immunoblotting demonstrated that only the two HCC cell lines that were sensitive to the effects of pre-miR-199a-3p were CD44+. Direct targeting of CD44 by miR-199a-3p was confirmed in HCC cell lines. In addition, transfection of miR-199a-3p into SNU449 cells reduced in vitro invasion and sensitized the cells to doxorubicin. In conclusion, identification of target genes of miR-132/-212 and miR-199a-3p may be useful for targeted therapy of PDAC and HCC, respectively. A miR-221study demonstrated the feasibility and therapeutic efficacy of selectively targeting a miRNA that is over-expressed in HCC using antisense oligonucleotides.
Thomas Schmittgen (Committee Chair)
Mamuka Kvaratskhelia (Committee Member)
Chenglong Li (Committee Member)
Kathleen A. Boris-Lawrie (Committee Member)

Recommended Citations

Citations

  • Park, J. K. (2012). Target Identification, Therapeutic Application and Maturation Mechanism of microRNAs [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331096696

    APA Style (7th edition)

  • Park, Jong Kook. Target Identification, Therapeutic Application and Maturation Mechanism of microRNAs. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1331096696.

    MLA Style (8th edition)

  • Park, Jong Kook. "Target Identification, Therapeutic Application and Maturation Mechanism of microRNAs." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1331096696

    Chicago Manual of Style (17th edition)

osu1331096696
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.