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Induction of alpha-methylacyl-CoA racemase by miR-138 via up-regulation of β-catenin in prostate cancer cells

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Alpha-methylacyl-CoA racemase (AMACR) is highly overexpressed in prostate cancer (PCa) and its transcriptional regulators include various transcription factors and CTNNB1/β-catenin. Our previous findings suggested a post-transcriptional regulation by the tumor-suppressive microRNA miR-138 in PCa. Thus, the aim of this study was to demonstrate the direct interaction of miR-138 with the 3′-UTR of AMACR. Furthermore, the influence of miR-138 on the expression of AMACR and selected AMACR regulators was investigated in PCa cells.

Methods

Using DU-145, PC-3, and LNCaP PCa cells, the effect of exogenous miR-138 on AMACR and selected AMACR regulators was determined by quantitative PCR and Western blot. Luciferase reporter assays were used to verify target and promoter interaction.

Results

Using a luciferase reporter assay a direct interaction of miR-138 with the AMACR-3′-UTR was confirmed. Surprisingly, AMACR expression was up-regulated by up to 125% by exogenous miR-138 in PCa cells. The lack of any miR-138 binding sites within the AMACR promoter suggested an indirect mechanism of up-regulation. Therefore, the effect of miR-138 on selected AMACR regulators including CTNNB1/β-catenin, RELA, SMAD4, SP1, and TCF4 was evaluated. MiR-138 solely evoked an up-regulation of CTNNB1 mRNA expression and β-catenin protein levels by up to 75%. Further in silico analysis revealed a binding site for miR-138 within the CTNNB1 promoter. MiR-138 could enhance the activity of the CTNNB1 promoter, which in turn could contribute to the observed AMACR up-regulation.

Conclusions

The present findings suggest that miR-138 can indirectly up-regulate AMACR via transcriptional induction of CTNNB1, at least in vitro in PCa cells.

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Acknowledgements

This work was funded by the Wilhelm Sander-Foundation (Grant Number: 2010.041.1). Intramural funding (MeDDriveGrant 2013) was provided by the Medizinische Fakultät Carl Gustav Carus (TU Dresden, Germany). Kati Erdmann also received financial support from the Förderverein Hilfe bei Prostatakrebs e.V. (Movember Campaign; Grant Number: MOV-2013-06) and was supported by the Medizinische Fakultät Carl Gustav Carus (TU Dresden, Germany) within the framework of the postdoctoral habilitation program for women. Furthermore, the authors are grateful to Andrea Lohse-Fischer and Ulrike Lotzkat for their excellent technical assistance.

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  1. Kati Erdmann and Knut Kaulke contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Germany

    Kati Erdmann, Knut Kaulke, Christiane Rieger, Manfred P. Wirth & Susanne Fuessel

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  1. Kati Erdmann
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  2. Knut Kaulke
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Correspondence to Kati Erdmann.

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Funding

This work was funded by the Wilhelm Sander-Foundation (Grant Number: 2010.041.1). Intramural funding (MeDDriveGrant 2013) was provided by the Medizinische Fakultät Carl Gustav Carus (TU Dresden, Germany). Kati Erdmann also received financial support from the Förderverein Hilfe bei Prostatakrebs e.V. (Movember Campaign; Grant Number: MOV-2013-06) and was supported by the Medizinische Fakultät Carl Gustav Carus (TU Dresden, Germany) within the framework of the postdoctoral habilitation program for women.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Erdmann, K., Kaulke, K., Rieger, C. et al. Induction of alpha-methylacyl-CoA racemase by miR-138 via up-regulation of β-catenin in prostate cancer cells. J Cancer Res Clin Oncol 143, 2201–2210 (2017). https://doi.org/10.1007/s00432-017-2484-5

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