Publication Date

2013-08-23

Availability

Embargoed

Embargo Period

2015-08-23

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2013-07-31

First Committee Member

Kerry L. Burnstein

Second Committee Member

Mary L. King

Third Committee Member

Derek M. Dykxhoorn

Fourth Committee Member

Pedro J. Salas

Fifth Committee Member

Yahia Daaka

Abstract

MicroRNAs (miRs) are small, endogenous, non-coding RNAs that regulate gene expressing by inhibiting the stability and/or translation of complementary mRNA targets. Expression of miR-23b/-27b, which are encoded in tandem as a cluster on chromosome 9, are specifically downregulated in metastatic prostate cancer tissue samples compared to benign prostate. MiR-23b/-27b levels are also lower in aggressive prostate cancer cell lines compared to more indolent cells. We show miR-23b/-27b suppress migration and invasion of two aggressive human prostate cancer cell lines. Furthermore, inhibition of miR-23b/-27b increases the migration and invasion potential of a less aggressive prostate cancer cell line. Interestingly, we found that the miR-23b/-27b cluster does not affect prostate cancer cell proliferation suggesting miR-23b/-27b are metastatic suppressors. We provide evidence that miR-23b/-27b suppress additional key tumorigenic processes. To understand the mechanism of miR-23b/-27b mediated suppression of metastatic cell processes, we examined the effects of miR-23b/-27b on Rac1, a Rho GTPase essential for the metastatic phenotype of prostate cancer cells. We show ectopic expression of miR-23b/-27b decrease Rac1 activity of aggressive prostate cancer cell lines while inhibition of these miRs increase Rac1 activity in a less aggressive prostate cancer cell line. In addition, we show that expression of miR-23b/-27b increase the cell adhesion protein E-cadherin, in two independent aggressive prostate cancer cell lines. Conversely inhibition of miR-23b/-27b in a less aggressive prostate cancer cell line decreases E-cadherin levels. These data establish an important role for miR-23b/-27b mediated-suppression of invasion and migration of aggressive prostate cancer cells. Since miRs have great potential use as biomarkers and drug targets or mimics, elucidating the role and mechanism of miR-23b/-27b in prostate cancer is critical in the development of novel and effective therapies and prognostic indicators.

Keywords

microrna; metastasis; prostate cancer; Rac1; E-cadherin

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