The androgen receptor (AR) plays an important role in the initiation and progression of prostate cancer (CaP). Preliminary data show that expression of microRNA Let-7c is downregulated in CaP cells and tissues compared to benign prostate. Let-7c suppresses AR expression and overexpression of let-7c reduces AR activity, suggesting that let-7c may contribute to AR modulation in CaP cells. Additional studies suggest that let-7c- mediated AR suppression is via c-myc, an AR activator that is consistently overexpressed in prostate cancer. In addition, let-7c decreases the growth of CaP cells in vitro and in vivo. Furthermore, analysis of specimens from human prostate indicates a reverse correlation between Let-7c and AR expression. These data suggest that Let-7c plays an important role in regulating AR signaling and the development and progression of CaP. This proposal is aimed at understanding a novel microRNA (miRNA) let-7c-myc- mediated AR signaling pathway and the interaction between them.
Three specific aims are proposed to this study.
Aim 1 is to determine the effect of let-7c on cell growth and androgen responsiveness. We will knockdown Let-7c expression in androgen- responsive human prostate cancer cell lines, and assess the effects of such downregulation on the growth and on the androgen responsiveness of the cells. Conversely, we will overexpress Let-7c in castration-resistant prostate cancer cells to determine whether it can suppress cell growth and cause a reversal to an androgen- dependent state.
Aim 2 is to characterize let-7c as a modulator of AR and c-myc. We will characterize the potential mechanisms of let-7c-mediated AR suppression and the role of c-myc in this process. We will study whether let-7c suppresses AR expression and its transcriptional functions, and whether it is via suppression of c-myc. We will determine whether let-7c directly targets c-myc RNA and whether c-myc recruitment to AR promoter is affected. Furthermore, we will explore how let-7c expression is regulated in prostate cancer cells.
Aim 3 is to determine the relationship between let-7c, AR, and c- myc expression and prostate cancer progression. We will test the relationship of Let-7c, AR and c-myc in clinical prostate cancer specimens, and determine whether the levels of these three important molecules correlate with disease progression and castration resistance in specimens from patients with prostate cancer. If a novel pathway that connects AR, c-myc, and microRNAs is identified, it will gain a better understanding of the molecular mechanisms leading to prostate cancer development and progression.

Public Health Relevance

Androgen receptor signaling plays critical roles in prostate development and cancer progression. We propose to explore the roles of microRNA let-7c in androgen receptor signaling and prostate cancer progression. Understanding the mechanisms of androgen receptor regulation and identification of molecular targets would greatly benefit to patients with prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA168601-03
Application #
8834827
Study Section
Urologic and Genitourinary Physiology and Pathology (UGPP)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2013-04-01
Project End
2016-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of California Davis
Department
Urology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Liu, Chengfei; Lou, Wei; Yang, Joy C et al. (2018) Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer. Nat Commun 9:4700
Lombard, Alan P; Liu, Liangren; Cucchiara, Vito et al. (2018) Intra versus Inter Cross-resistance Determines Treatment Sequence between Taxane and AR-Targeting Therapies in Advanced Prostate Cancer. Mol Cancer Ther 17:2197-2205
Tummala, Ramakumar; Lou, Wei; Gao, Allen C et al. (2017) Quercetin Targets hnRNPA1 to Overcome Enzalutamide Resistance in Prostate Cancer Cells. Mol Cancer Ther 16:2770-2779
Armstrong, Cameron M; Liu, Chengfei; Lou, Wei et al. (2017) MicroRNA-181a promotes docetaxel resistance in prostate cancer cells. Prostate 77:1020-1028
Liu, Chengfei; Armstrong, Cameron M; Lou, Wei et al. (2017) Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer. Mol Cancer Ther 16:1521-1530
Liu, Chengfei; Armstrong, Cameron M; Lou, Wei et al. (2017) Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer. Mol Cancer Ther 16:35-44
Lombard, Alan P; Liu, Chengfei; Armstrong, Cameron M et al. (2017) ABCB1 Mediates Cabazitaxel-Docetaxel Cross-Resistance in Advanced Prostate Cancer. Mol Cancer Ther 16:2257-2266
Wang, Junjian; Zou, June X; Xue, Xiaoqian et al. (2016) ROR-? drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. Nat Med 22:488-96
Tummala, Ramakumar; Nadiminty, Nagalakshmi; Lou, Wei et al. (2016) Lin28 induces resistance to anti-androgens via promotion of AR splice variant generation. Prostate 76:445-55
Armstrong, Cameron M; Gao, Allen C (2016) Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer. Asian J Urol 3:185-194

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