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REGULATION OF ANDROGEN SIGNALING AND CHOLESTEROL METABOLISM BY MIR-149-5P IN PROSTATE CANCER

Singh, Savita, Singh
http://rave.ohiolink.edu/etdc/view?acc_num=csu1513271812361131

Abstract Details

2017, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Prostate cancer growth and proliferation depend on androgen signaling mediated by transactivation of androgen receptor (AR). Androgen ablation remains the mainstay therapy for treatment of the disease. However, despite androgen ablation, the disease relapses to more aggressive form known as castration-resistant prostate cancer (CRPC). Androgen Signaling Inhibitor (ASI) such as abiraterone and enzalutamide are the most effective treatment methods for CRPC. However, more than one-third of CRPC patients develop resistance to these treatments mostly due to the gain of function in the AR protein and increase in intratumoral dihydrotestosterone (DHT) synthesis. Intratumoral DHT synthesis from steroid precursors in tumors is augmented by up-regulation of intracellular cholesterol promoted by SREBP1, and its regulated genes together with an influx of cholesterol supported by SCARB1. Tumor-specific downregulation of microRNAs which control the AR and steroid biosynthesis appears to promote tumor growth and resistance to therapeutics in CRPC. We have investigated the role of miR-149-5p for its anti-proliferative potential in PCa. We have observed down-regulation of miR-149-5p in prostate tumors and discovered that it targets AR and key proteins involved in maintaining cholesterol homeostasis, such as SREBP1, HMGCR, HMGCS1, and SCARB1. Ectopic expression of miR-149-5p inhibits invasion and proliferation of PCa cells, alone as well as in combination with AR antagonist enzalutamide. We further explored the regulation of AR signaling and cholesterol metabolism by miR-149-5p in a PCa mice model. Our results indicate a significant suppression of intratumoral cholesterol, testosterone, and DHT in tumors treated with miR-149-5p, indicating its tumor suppressive function. This study provides evidence that miR-149-5p may serve as an adjuvant therapeutic agent for CRPC in combination with ASIs.
Girish Shukla, Ph.D. (Advisor)
Justin Lathia, Ph.D. (Committee Member)
Anton Komar, Ph.D. (Committee Member)
Roman Kondratov, Ph.D. (Committee Member)
Crystal Weyman, Ph.D. (Other)
Bin Su, Ph.D. (Other)
Biology; Molecular Biology

Recommended Citations

Citations

  • Singh, Singh, S. (2017). REGULATION OF ANDROGEN SIGNALING AND CHOLESTEROL METABOLISM BY MIR-149-5P IN PROSTATE CANCER [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1513271812361131

    APA Style (7th edition)

  • Singh, Singh, Savita. REGULATION OF ANDROGEN SIGNALING AND CHOLESTEROL METABOLISM BY MIR-149-5P IN PROSTATE CANCER . 2017. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1513271812361131.

    MLA Style (8th edition)

  • Singh, Singh, Savita. "REGULATION OF ANDROGEN SIGNALING AND CHOLESTEROL METABOLISM BY MIR-149-5P IN PROSTATE CANCER ." Doctoral dissertation, Cleveland State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=csu1513271812361131

    Chicago Manual of Style (17th edition)

csu1513271812361131
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© 2017, some rights reserved.Creative Commons License REGULATION OF ANDROGEN SIGNALING AND CHOLESTEROL METABOLISM BY MIR-149-5P IN PROSTATE CANCER by Savita Singh Singh is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Cleveland State University and OhioLINK.