Androgen dihydrotestosterone (DHT) promotes the bladder cancer nuclear AR-negative cell invasion via a newly identified membrane androgen receptor (mAR-SLC39A9)-mediated Gαi protein/MAPK/MMP9 intracellular signaling

AbstractAndrogen-deprivation therapy (ADT) via targeting androgens/androgen receptor (AR) signals may suppress cell proliferation in both prostate cancer (PCa) and bladder cancer (BCa), yet its impact on the cell invasion of these two urological cancers remains unclear. Here we found targeting androgens/AR with either the recently developed antiandrogen Enzalutamide (Enz) or AR-shRNAs led to increase PCa cell invasion, yet decrease BCa cell invasion. Mechanistic dissection revealed that suppressing androgens/AR signals could result in differential alterations of the selective circular RNAs (circRNAs) as a result of differential endogenous AR transcription. A negative autoregulation in PCa, yet a positive autoregulation in BCa, as a result of differential binding of AR to different androgen-response elements (AREs) and a discriminating histone H3K4 methylation, likely contributes to this outcome between these two urological tumors. Further mechanistic studies indicated that AR-encoded circRNA-ARC1 might sponge/alter the availability of the miRNAs miR-125b-2-3p and/or miR-4736, to impact the metastasis-related PPARγ/MMP-9 signals to alter the PCa vs. BCa cell invasion. The preclinical study using the in vivo mouse model confirms in vitro cell lines data, showing that Enz treatment could increase PCa metastasis, which can be suppressed after suppressing circRNA-ARC1 with sh-circRNA-ARC1. Together, these in vitro/in vivo results demonstrate that antiandrogen therapy with Enz via targeting AR may lead to either increase PCa cell invasion or decrease BCa cell invasion. Targeting these newly identified AR/circRNA-ARC1/miR-125b-2-3p and/or miR-4736/PPARγ/MMP-9 signals may help in the development of new therapies to better suppress the Enz-altered PCa vs. BCa metastasis.

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Sex Hormone Receptor Signaling in Bladder Cancer: A Potential Target for Enhancing the Efficacy of Conventional Non-Surgical Therapy

Cells ◽

10.3390/cells10051169 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1169

Author(s):

Hiroki Ide ◽

Hiroshi Miyamoto

Keyword(s):

Bladder Cancer ◽

Estrogen Receptor ◽

Androgen Receptor ◽

Surgical Therapy ◽

Urothelial Cancer ◽

Hormone Receptors ◽

Estrogen Receptor Α ◽

Vital Role ◽

Sex Hormone ◽

Sex Steroid Hormone

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

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lncRNA ADAMTS9-AS1 promotes bladder cancer cell invasion, migration, and inhibits apoptosis and autophagy through PI3K/AKT/mTOR signaling pathway

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2021.106069 ◽

2021 ◽

pp. 106069

Author(s):

Fan Zhou ◽

Zijian Li ◽

Lizhi Dong ◽

Guoqing Yang

Keyword(s):

Bladder Cancer ◽

Signaling Pathway ◽

Cancer Cell ◽

Cell Invasion ◽

Mtor Signaling ◽

Bladder Cancer Cell ◽

Cancer Cell Invasion ◽

Mtor Signaling Pathway

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Androgen Receptor (AR) Transcriptionally Inhibits Programmed Death Ligand-1(PD-L1) Expression to Impact Bladder Cancer Cell Immune Escape

SSRN Electronic Journal ◽

10.2139/ssrn.3946279 ◽

2021 ◽

Author(s):

Anran Sun ◽

Yu Luo ◽

Wen Xiao ◽

Zhipeng Zhu ◽

Hongyu Yan ◽

...

Keyword(s):

Bladder Cancer ◽

Androgen Receptor ◽

Cancer Cell ◽

Immune Escape ◽

Bladder Cancer Cell ◽

Programmed Death Ligand 1 ◽

Programmed Death

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The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR)

Cellular Physiology and Biochemistry ◽

10.1159/000480419 ◽

2017 ◽

Vol 43 (1) ◽

pp. 405-418 ◽

Cited By ~ 46

Author(s):

Yaoyao Xiong ◽

Long Wang ◽

Yuan Li ◽

Minfeng Chen ◽

Wei He ◽

...

Keyword(s):

Bladder Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Cancer Growth ◽

Invasion And Migration ◽

Non Coding Rna ◽

Bladder Cancer Cells ◽

And Migration ◽

Cancer Tissues ◽

Long Non Coding Rna

Backgrounds/Aims: Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA’s target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. Methods: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. Results: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells’ proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3’UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. Conclusion: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation.

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Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways

Molecular Endocrinology ◽

10.1210/me.2008-0160 ◽

2008 ◽

Vol 22 (11) ◽

pp. 2448-2465 ◽

Cited By ~ 52

Author(s):

Ramesh Narayanan ◽

Christopher C. Coss ◽

Muralimohan Yepuru ◽

Jeffrey D. Kearbey ◽

Duane D. Miller ◽

...

Keyword(s):

Androgen Receptor ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Levator Ani ◽

Reproductive Organs ◽

Cross Reactivity ◽

Levator Ani Muscle ◽

Xenopus Laevis Oocyte ◽

Muscle Weight

Abstract Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

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Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis

Oncogene ◽

10.1038/s41388-019-1120-z ◽

2019 ◽

Vol 39 (9) ◽

pp. 1983-1996 ◽

Cited By ~ 8

Author(s):

Rui Yang ◽

Jiheng Xu ◽

Xiaohui Hua ◽

Zhongxian Tian ◽

Qipeng Xie ◽

...

Keyword(s):

Bladder Cancer ◽

Cell Invasion ◽

Biological Significance ◽

Protein Translation ◽

Mechanistic Studies ◽

Mrna Transcription ◽

Ongoing Development ◽

Muscle Invasive ◽

Dicer Expression ◽

New Strategies

AbstractInvasive bladder cancer (BC) is one of the most lethal malignant urological tumors. Although miR-200a has been reported as an onco-miRNA that targets the PTEN gene in endometrioid carcinoma, its biological significance in BC invasion has been poorly explored. In the current study, we found that miR-200a was markedly overexpressed in both human BC tissues and BBN-induced muscle-invasive BC tissues. We further showed that miR-200a overexpression specifically promoted human BC cell invasion, but not migration, via transcriptional upregulation of matrix metalloproteinase (MMP)-2. Mechanistic studies indicated that the increased phosphorylation of c-Jun mediated the increasing levels of MMP-2 mRNA transcription. Further investigation revealed that Dicer was decreased in miR-200a overexpressed BC cells; this resulted in inhibition of miR-16 maturation and consequently led to increased JNK2 protein translation and c-Jun activation. Taken together, the studies here showed that miR-200a overexpression inhibited Dicer expression, in turn, resulted in inhibition of miR-16 maturation, leading to upregulation of JNK2 expression, c-Jun phosphorylation, MMP-2 transcription and, ultimately, BC invasion. Collectively, these results demonstrate that miR-200a is an onco-miRNA that is a positive regulator for BC invasion. This finding could be very useful in the ongoing development of new strategies to treat invasive BC patients.

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