Publication Date

2016-03-30

Availability

Embargoed

Embargo Period

2018-03-30

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2016-03-16

First Committee Member

Kerry L. Burnstein

Second Committee Member

Xin-Hai Pei

Third Committee Member

Enrique Mesri

Fourth Committee Member

Priyamvada Rai

Fifth Committee Member

Chad Ritch

Abstract

Deregulation of microRNAs contributes to progression and metastasis of prostate and other cancers. MiR-23b and miR-27b, encoded in the same miR cluster (miR-23b/-27b), are down-regulated in human metastatic prostate cancer compared to primary tumors and benign tissue. Expression of miR-23b/-27b decreases cell migration, invasion and results in anoikis resistance. Conversely, antagomiR-mediated miR-23b and -27b silencing produces the opposite result in a more indolent prostate cancer cell line. However, neither miR-23b/-27b expression nor inhibition impacts prostate cancer cell proliferation or viability suggesting that miR-23b/-27b selectively suppresses metastasis. To examine the effects of miR-23b/-27b on prostate cancer metastasis in vivo, orthotopic prostate xenografts were established using aggressive prostate cancer cells transduced with miR-23b/-27b or non-targeting control miRNA. While primary tumor formation was similar between miR-23b/-27b-transduced cells and controls, miR-23b/-27b expression in prostate cancer cells decreased seminal vesicle invasion and distant metastases. Gene expression profiling identified the endocytic adaptor, Huntingtin interacting protein 1 related (HIP1R) as being down-regulated by miR-23b/-27b. Ectopic HIP1R expression in prostate cancer cells inversely phenocopied the effects of miR-23b/-27b overexpression on migration, invasion, and anchorage-independent growth. HIP1R rescued miR-23b/-27b mediated repression of migration in aggressive prostate cancer cells. HIP1R mRNA levels were decreased in seminal vesicle tissue from mice bearing miR-23b/-27b-transduced prostate cancer cell xenografts compared with scrambled controls, suggesting HIP1R is a key functional target of miR-23b/-27b. In addition, depletion of HIP1R led to a more rounded, less mesenchymal-like cell morphology, consistent with decreased metastatic properties. Together, these data demonstrate that the miR-23b/-27b cluster targets hip1r and functions as a metastasis-suppressor in pre-clinical models of prostate cancer.

Keywords

Prostate Cancer; Metastasis; microRNA; HIP1R; Invasion

Available for download on Friday, March 30, 2018

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