A modified yeast assay used on archival samples of localized prostate cancer tissue improves the detection of <i>p53</i> abnormalities and increases their predictive value

Shi, Xu; Gandour‐Edwards, Regina; Beckett, Laurel A.; Deitch, Arline D.; White, Ralph W. deVere

doi:10.1111/j.1464-410x.2004.05093.x

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…We, as well as others 39, validated that miR‐125b is a direct, negative regulator of wild‐type p53 by suppressing its basal expression and up‐regulation in response to pro‐apoptotic stimuli. Here, we asked how aberrant miR‐125b expression affects apoptosis in CaP cells harboring a p53 mutation Addressing this issue is of clinical importance, since mutation of p53 occurs in more than 40% of CaPs 44–46. At present, the exact answer to this question has not been determined.…”

Section: Discussionmentioning

confidence: 99%

miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes

Shi¹,

Xue²,

Hong³

et al. 2010

The Prostate

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174

148

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BACKGROUND Increasing evidence demonstrates that aberrantly-regulated microRNAs (miRNAs) contribute to the initiation and progression of human cancer. We previously have demonstrated that miR-125b stimulated the growth of prostate cancer (CaP) cells. In this study, we further determined the influence of miR-125b on the pathogenesis of prostate cancer. METHODS To evaluate the effect of miR-125b on xenograft tumor growth, male athymic mice were subcutaneously injected with PC-346C-miR-125b cells that stably overexpressed miR-125b. Potential direct target transcripts of miR-125b were identified using a bioinformatics approach and three miR-125b targeted molecules were confirmed by means of biochemical analyses. RESULTS Enforced expression of miR-125b promoted tumor growth in both intact and castrated male nude mice. In an effort to define the molecular mechanism(s) mediating its tumor growth properties, we found that miR-125b directly targets eight transcripts, including three key pro-apoptotic genes: p53, Puma and Bak1. Increasing the abundance of miR-125b resulted in a dramatic decrease in the levels of these three proteins in prostate cancer cells. A direct repressive effect on each of these was supported by the ability of miR-125b to significantly reduce the activity of luciferase reporters containing their 3′-untranslated regions of each gene encompassing the miR-125b-binding sites. Additionally, we found that repression of miR-125b activity was able to sensitize prostate cancer cells to different therapeutic interventions. CONCLUSION Data obtained in this study demonstrate that miR-125b promotes growth of prostatic xenograft tumors by down-regulating three key pro-apoptotic genes. This suggests that miR-125b is oncogenic and makes it an attractive therapeutic target in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes

Shi¹,

Xue²,

Hong³

et al. 2010

The Prostate

Self Cite

174

148

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“…Androgen depletion/ablation leads to increased level of neuroendocrine cells in vitro (Yuan et al, 2006) and in vivo (Huss et al, 2004), and abundant literature suggests that increased level of neuroendocrine differentiation in prostate cancer is associated with progression towards an AI state (di Sant'Agnese and Cockett, 1996). Mutation of p53 is another hallmark of prostate cancer progression (Shi et al, 2004), the most common mutation found in prostate cancer is p53-R273H (Dinjens et al, 1994). When stably transfected into androgen-sensitive cell lines, such as LNCaP and PC-346C, this mutant causes an upregulation of H2-relaxin and its receptor LGR7 (Vinall et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

Liu¹,

Vinall²,

Tepper³

et al. 2007

Oncogene

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We have previously demonstrated that human H2-relaxin can mediate androgen-independent growth of LNCaP through a mechanism that involves the activation of the androgen receptor (AR) signaling pathway. The goal of the current study is to elucidate the mechanism(s) by which H2-relaxin causes activation of the AR pathway. Our data indicate that there is cross-talk between AR and components of the Wnt signaling pathway. Addition of H2-relaxin to LNCaP cells resulted in increased phosphorylation of protein kinase B (Akt) and inhibitory phosphorylation of glycogen synthase kinase-3b (GSK-3b) with subsequent cytoplasmic accumulation of b-catenin. Immunoprecipitation and immunocytochemical studies demonstrated that the stabilized b-catenin formed a complex with AR, which was then translocated into the nucleus. Chromatin immunoprecipitation analysis determined that the AR/b-catenin complex binds to the proximal region of the prostatespecific antigen promoter. Inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, using LY294002, prevented both H2-relaxin-mediated phosphorylation of Akt and GSK-3b and translocation of b-catenin/AR into the nucleus. Knockdown of b-catenin levels using a b-cateninspecific small interfering RNA inhibited H2-relaxin-induced AR activity. The combined data demonstrate that PI3K/ Akt and components of the Wnt pathway can facilitate H2-relaxin-mediated activation of the AR pathway.

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“…p53: The importance of p53 mutation and loss on cancer development and progression is well established, and in prostate cancer mutations of p53 have been identified in 45% of radical prostatectomy samples (Shi et al 2004). However, as with PTEN, the AR repressor function is confounded by its role as tumor-suppressor protein.…”

Section: Corepressors and Prostate Cancermentioning

confidence: 99%

Androgen receptor corepressors and prostate cancer

Burd¹,

Morey²,

Knudsen³

2006

Endocr Relat Cancer

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The androgen receptor (AR) mediates the effects of male steroid hormones (androgens) and contributes to a wide variety of physiological and pathophysiological conditions. As such, the regulatory mechanisms governing AR activity are of high significance. Concerted effort has been placed on delineating the mechanisms that control AR activity in prostate cancer, as AR is required for survival and proliferation in this tumor type. Moreover, AR is the central therapeutic target for metastatic prostate cancers, and recurrent tumors evade therapy by restoring AR activity. It is increasingly apparent that AR cofactors which modulate receptor activity can contribute to prostate cancer growth or progression, and this has been particularly well established for AR coactivators. The present review is focused on the role of AR corepressors in governing androgen action, with a specific emphasis on their activities in prostate cancer.

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A modified yeast assay used on archival samples of localized prostate cancer tissue improves the detection of p53 abnormalities and increases their predictive value

Cited by 9 publications

References 28 publications

miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes

miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes

Inappropriate activation of androgen receptor by relaxin via β-catenin pathway

Androgen receptor corepressors and prostate cancer

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