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Investigation of Micro-RNA-based Approaches to Overcome Epithelial-Mesenchymal Transition in Pancreatic Cancer

Mody, Hardik R
http://orcid.org/0000-0002-7910-523X
http://rave.ohiolink.edu/etdc/view?acc_num=osu1502908907944535

Abstract Details

2017, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Pancreatic Cancer is one of the most devastating type of cancers with an extremely poor 5-year survival rate of about 7%. This is largely due to the metastatic ability of pancreatic cancers which renders approved drugs like gemcitabine ineffective. It is well-known that Epithelial-Mesenchymal Transition (EMT), a cellular trans-differentiation process, contributes not only to the metastatic spread but also to increased drug resistance. Hence, suppressing EMT is likely to be beneficial for therapeutic purposes in pancreatic cancer. In the present dissertation study, we have utilized microRNA-(18-20 nucleotides long, non-coding RNAs) based approaches to target EMT of pancreatic cancer. In the first part of the study, we utilized a small molecule histone methyl transferase inhibitor, 3-Deazaneplanocin-A (DNZep) to decrease Transforming Growth Factor-beta1 (TGF-ß1) ligand (main inducers of EMT), TGF-ß Receptors (TGFBR1 and TGFBR2) protein levels, suppress TGF-ß signaling, and thereby TGF-ß1-induced EMT in pancreatic cancer. We identified epigenetic reprogramming of miRNAs, especially miR-663a, miR-4787-5p, as well as miR-202-5p, in DZNep’s suppression of EMT. While miR-663a and miR-4787-5p directly targeted TGF-ß1, miR-202-5p targeted both TGFBR1 and TGFBR2 to inhibit EMT in pancreatic cancer. Next, we identified SET onco-protein to contribute to the process of EMT via multiple mechanisms and members of let-7 family (let-7e, let-7f-2, and let-7i) to target SET in pancreatic cancer. Hence, we identified a potential interplay of let-7 miRNAs and SET (let-7-SET interplay) that could be targeted to suppress EMT of multiple cancer types. In the later part of the study, we identified a liver-specific miRNA, miR-122 as one of the most downregulated miRNAs in Pancreatic Ductal Adeno Carcinoma (PDAC) patients. Consistently, overexpression of miR-122 suppressed growth as well as EMT characteristics in PDAC cell lines as well as mouse models. Finally, we utilized gold nanoparticle (Au NP) platform to deliver miRNAs (e.g. let-7e) to evaluate the feasibility of utilizing miRNA-based approaches to suppress EMT, though extensive work is still required for translational purposes.
Rajgopal Govindarajan (Advisor)
Sharyn Baker (Committee Member)
Moray Campbell (Committee Member)
Kalpana Ghoshal (Committee Member)
Peixuan Guo (Committee Member)
254 p.
Pharmaceuticals; Pharmacy Sciences
Pancreatic Cancer, Micro-RNA, Epithelial-Mesenchymal Transition

Recommended Citations

Citations

  • Mody, H. R. (2017). Investigation of Micro-RNA-based Approaches to Overcome Epithelial-Mesenchymal Transition in Pancreatic Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1502908907944535

    APA Style (7th edition)

  • Mody, Hardik. Investigation of Micro-RNA-based Approaches to Overcome Epithelial-Mesenchymal Transition in Pancreatic Cancer. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1502908907944535.

    MLA Style (8th edition)

  • Mody, Hardik. "Investigation of Micro-RNA-based Approaches to Overcome Epithelial-Mesenchymal Transition in Pancreatic Cancer." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1502908907944535

    Chicago Manual of Style (17th edition)

osu1502908907944535
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© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.