Date of Award

2014

Document Type

Open Access Thesis

Department

College of Pharmacy

Sub-Department

Pharmaceutical Science

First Advisor

Michael Shtutman

Abstract

Micro RNA are small single stranded RNA that regulate the expression of various genes. MiRNA guide the mRNA disintegrating RISC complex to the complimentary sequence in the target mRNA. Each micro RNA has multiple targets and can play a different biological role depending on the population of targets at the particular stage of the cell or a physiological state. Several miRNA show elevated or decreased levels of expression in various cancers because of their role in tumor initiation and progression. MiRNA belonging to mir148/152 family are examples of such MicroRNA. This family includes miR148a, miR148b and miR152. MiR148a and miR152 are down-regulated in various cancers while there is no significant change in the expression of miR148b. Prior studies indicate a role for miR152 and mir148a in suppressing tumor growth in various cancers. However, the mechanism of action and targets remain to be identified.

Interestingly, miR148b and miR152 are encoded within the first intron of COPZ1 and COPZ2 genes respectively. This study started with the understanding of the role of miR152 in cancer progression. COPZ2 gene expression is lower in malignant tissues of different tumor types when compared to benign tumors suggesting a similar expression pattern for miR152. We have identified several candidate targets for miR152 in the TGF-β pathway including DNMT1, LTBP1, SERPINE1 and the Rho GEF -LARG. This data led to the hypothesis that miR152 expression correlates with tumor progression and

that miR152 suppresses epithelial to mesenchymal transition (EMT) and EMT related events through regulation of specific EMT mediators and effectors. However, all the members belonging to this family have the same seed sequence that binds to the target genes, suggesting that they play similar roles and have common targets.

In this thesis, I have verified LTBP1 and PAI1 as novel, common targets for the miR148/152 family. Additionally, reintroduction of these microRNA into prostate cancer cell lines can decrease the migratory capabilities and increase the adhesive characteristics. This biological role of these miRNA can be exploited in the form of replacement miRNA in cancer therapy.

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