Dataset Information

MiR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2.

ABSTRACT: Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating androgen deprivation. Furthermore, miR-125b expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LNCaP prostate cancer cells treated with the antiandrogen bicalutamide. Using LNCaP cells, the effect of miR-125b modulation on apoptotic protein and NCOR2, a co-repressor of androgen receptor (AR), was examined by Western blot. A 3'-untranslated region (UTR) luciferase-binding assay was performed to confirm that miR-125b targets NCOR2. We found that surgical castration induced an initial increase in the expression of circulating miR-125b in mice, while sham surgery did not. In addition, AR blockade via bicalutamide was associated with the rapid release of miR-125b into the cell culture medium of prostate cancer cells. A previously studied target of miR-125b, a regulator in the apoptotic pathway, BAK1, could not completely account for the role of miR-125b in prostate cancer. Thus, we looked for additional targets of miR-125b and found that NCOR2, which is a repressor of AR, is a direct target of miR-125b. We found that NCOR2 protein expression was blocked by mimics of miR-125b, and a luciferase-binding assay confirmed that NCOR2 is a direct target of miR-125b. Our data provide novel evidence that miR-125b is an important regulator of the AR with specific ramification for the effectiveness of antiandrogens and other hormonal therapies in prostate cancer.

SUBMITTER: Yang X

PROVIDER: S-EPMC3559200 | biostudies-other | 2012 Apr

REPOSITORIES: biostudies-other

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miR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2.

Yang Xiaoping X Bemis Lynne L Su Lih-Jen LJ Gao Dexiang D Flaig Thomas W TW

BioResearch open access 20120401 2

Recognition of micro-RNA function and their contribution to the biology of disease has given a new insight into disease mechanisms, with these discoveries potentially improving clinical diagnostic and therapeutic options. miR-125b has been identified as an important regulator in various cancers, including prostate cancer, but the mechanism of this regulation remains incompletely understood. In these studies, the effect of castration on miR-125b serum expression was evaluated in mice, simulating ...[more]

PMID: 23514806

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Project description:BackgroundAmorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described.ResultsWe first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation.ConclusionsOur findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.

Project description:BACKGROUND:Prostate epithelial cells depend on androgens for survival and function. In (early) prostate cancer (PCa) androgens also regulate tumor growth, which is exploited by hormonal therapies in metastatic disease. The aim of the present study was to characterize the androgen receptor (AR) response in hormonal therapy-resistant PC346 cells and identify potential disease markers. METHODOLOGY/PRINCIPAL FINDINGS:Human 19K oligoarrays were used to establish the androgen-regulated expression profile of androgen-responsive PC346C cells and its derivative therapy-resistant sublines: PC346DCC (vestigial AR levels), PC346Flu1 (AR overexpression) and PC346Flu2 (T877A AR mutation). In total, 107 transcripts were differentially-expressed in PC346C and derivatives after R1881 or hydroxyflutamide stimulations. The AR-regulated expression profiles reflected the AR modifications of respective therapy-resistant sublines: AR overexpression resulted in stronger and broader transcriptional response to R1881 stimulation, AR down-regulation correlated with deficient response of AR-target genes and the T877A mutation resulted in transcriptional response to both R1881 and hydroxyflutamide. This AR-target signature was linked to multiple publicly available cell line and tumor derived PCa databases, revealing that distinct functional clusters were differentially modulated during PCa progression. Differentiation and secretory functions were up-regulated in primary PCa but repressed in metastasis, whereas proliferation, cytoskeletal remodeling and adhesion were overexpressed in metastasis. Finally, the androgen-regulated genes ENDOD1, MCCC2 and ACSL3 were selected as potential disease markers for RT-PCR quantification in a distinct set of human prostate specimens. ENDOD1 and ACSL3 showed down-regulation in high-grade and metastatic PCa, while MCCC2 was overexpressed in low-grade PCa. CONCLUSIONS/SIGNIFICANCE:AR modifications altered the transcriptional response to (anti)androgens in therapy-resistant cells. Furthermore, selective down-regulation of genes involved in differentiation and up-regulation of genes promoting proliferation and invasion suggest a disturbed balance between the growth and differentiation functions of the AR pathway during PCa progression. These findings may have implications in the current treatment and development of novel therapeutical approaches for metastatic PCa.

Dataset Information

MiR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2.

Publications

miR-125b Regulation of Androgen Receptor Signaling Via Modulation of the Receptor Complex Co-Repressor NCOR2.

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