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Jey Sabith Ebron_Dissertation.pdf (7.7 MB)

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Regulation of Androgen Signaling and Interacting Factors by miRNA for Prostate Cancer Therapeutics

Ebron, Jey Sabith
http://orcid.org/0000-0002-5820-4175
http://rave.ohiolink.edu/etdc/view?acc_num=csu1495118344389254

Abstract Details

2017, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Androgen receptor (AR) is a member of the steroid receptor family that plays a significant role in castration-sensitive and castration-resistant prostate cancer (CRPC). Therefore, targeting Androgen signaling axis and AR transactivation function remains an attractive therapeutic option. Numerous studies have demonstrated AR protein function in prostate cancer (PCa), however not much is known about AR mRNA structure-feature and metabolism. In this study, we embarked on understanding the role of AR 3’ untranslated region in AR gene expression by identifying 3’ UTR regions that can be therapeutically targeted at the post-transcriptional level. Additionally, due to the molecular heterogeneity of PCa, we envisaged to target critical PCa specific cellular pathways using a common antagonist miR-644a. We show that the novel primate-specific miRNA (miR-644a), modulates expression of a diverse set of oncogenic pathways in PCa including androgen signaling, AKT/IGF-1R signaling, c-Myc expression and epithelial-mesenchymal transition (EMT). We determined that miR-644a negatively regulates the AR signaling cascade by directly targeting of expression of AR, and its coregulators. In addition, miR-644a negatively regulates expression of c-Myc, Akt, IGF-1R, GAPDH and antiapoptotic factors Bcl-xl and Bcl-2 as well as EMT promoting factors including ZEB1, cdk6, and Snail. Intratumoral delivery of miR-644a demonstrates a profound tumor suppressor function in PCa mouse xenografts. In summary, this study demonstrates a distinct advantage of utilizing miRNAs as a therapeutic option to treat cancers of heterogeneous origins, such as cancer of the prostate.
Girish Shukla, Ph.D. (Advisor)
Barsanjit Mazumder, Ph.D. (Committee Member)
Alexandru Almasan, Ph.D. (Committee Member)
Roman Kondratov, Ph.D. (Committee Member)
Hannelore Heemers, Ph.D. (Committee Member)
Sanjay Gupta, Ph.D. (Committee Member)
181 p.
Biology; Molecular Biology
Androgen Receptor; miRNA; CRPC; PCa heterogeneity

Recommended Citations

Citations

  • Ebron, J. S. (2017). Regulation of Androgen Signaling and Interacting Factors by miRNA for Prostate Cancer Therapeutics [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1495118344389254

    APA Style (7th edition)

  • Ebron, Jey Sabith. Regulation of Androgen Signaling and Interacting Factors by miRNA for Prostate Cancer Therapeutics. 2017. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1495118344389254.

    MLA Style (8th edition)

  • Ebron, Jey Sabith. "Regulation of Androgen Signaling and Interacting Factors by miRNA for Prostate Cancer Therapeutics." Doctoral dissertation, Cleveland State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=csu1495118344389254

    Chicago Manual of Style (17th edition)

csu1495118344389254
225
© 2017, all rights reserved.
This open access ETD is published by Cleveland State University and OhioLINK.