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The Consequence of Loss of Expression of AR-targeting MicroRNAs in Prostate Cancer Progression

Prostate Cancer (PCa) is the most common cancer that affect men worldwide. As PCa depends on androgen receptor (AR) signaling, AR blockade remains the prime choice for PCa therapy. Nonetheless, treatment failure is common and warrants a better understanding of the molecular underpinnings of AR and other key signaling pathways in PCa. Non-coding RNAs, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles as master regulators of protein coding and noncoding gene expression. Previous studies in our lab identified downregulation of AR-targeting miRNAs, miR-299-3p, miR-30e and miR-34c in PCa tumors, particularly in African American compared to Caucasian PCa patients. Here we show that miR-299-3p and miR-30e exert their tumor suppressor functions through modulation of a variety of signaling pathways through regulation of genes including VEGFA, PI3K/Akt, FBXO45, PARPBP and MYBL2 and other downstream effector genes in addition to AR using in vitro and in vivo xenograft models. We showed validation of miR-299-3p and miR-30e interactions with and functional regulation of the target mRNAs associated with phenotypic changes in PCa cells through overexpression and knockdown approaches. We showed improved drug sensitivity of PCa cells upon restored expression of miRNAs. We provide evidence on the role of two novel miRNA-interacting lncRNAs HELLPAR and PAINT in modulating key signaling pathways that could significantly impact PCa progression. We also demonstrate that loss of expression of miR-299-3p and miR-34c in PCa tumors, that also show racial disparity, is associated with promoter hypermethylation mediated through DNA Methyltransferase (DNMT) activation and expression. We show that miR-299-3p and miR-30e target DNMT3A and DNMT3B and loss of miRNA expression stabilizes DNMT expression suggesting a double-negative feedback loop that leads to further silencing of miRNA expression. This study show involvement of a novel miRNA/lncRNA/mRNA network in PCa progression, which can be used as prognostic marker for aggressive PCa.
Date01 January 2021
CreatorsGanapathy, Kavya
Source SetsUniversity of Central Florida
Detected LanguageEnglish
SourceElectronic Theses and Dissertations, 2020-

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