Oncotarget

Research Papers:

Role of miR-34a as a suppressor of L1CAM in endometrial carcinoma

Uwe Schirmer, Kai Doberstein, Anne-Kathleen Rupp, Niko P. Bretz, Daniela Wuttig, Helena Kiefel, Christian Breunig, Heidi Fiegl, Elisabeth Müller-Holzner, Robert Zeillinger, Eva Schuster, Alain G. Zeimet, Holger Sültmann and Peter Altevogt _

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Oncotarget. 2014; 5:462-472. https://doi.org/10.18632/oncotarget.1552

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Abstract

Uwe Schirmer1, Kai Doberstein1, Anne-Kathleen Rupp1, Niko P. Bretz1, Daniela Wuttig2, Helena Kiefel1, Christian Breunig5, Heidi Fiegl3, Elisabeth Müller-Holzner3, Robert Zeillinger4, Eva Schuster4, Alain G. Zeimet3, Holger Sültmann2 and Peter Altevogt1

1 Department of Translational Immunology, German Cancer Research Center;

2 Working Group Cancer Genome Research, German Cancer Research Center;

3 Department of Gynecology and Obstetrics, Medical University of Innsbruck, A-6020 Innsbruck, Austria,

4 Medical University Vienna, Vienna, Austria;

5 Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany

Correspondence:

Peter Altevogt, email:

Key words: miR-34a, endometrial carcinoma, L1CAM, ovarian carcinoma

Received: November 4, 2013 Accepted: January 12, 2014 Published:January 12, 2014

Abstract

L1CAM promotes cell motility, invasion and metastasis formation in various human cancers and can be considered as a driver of tumor progression. Knowledge about genetic processes leading to the presence of L1CAM in cancers is of considerable importance. Experimentally, L1CAM expression can be achieved by various means. Overexpression of the transcription factor SLUG or treatment of cells with TGF-β1 can induce or augment L1CAM levels in cancer cells. Likewise, hypomethylation of the L1CAM promoter on the X chromosome correlates with L1CAM expression. However, presently no mechanisms that might control transcriptional activity are known. Here we have identified miR-34a as a suppressor of L1CAM. We observed that L1CAM positive endometrial carcinoma (EC) cell lines HEC1B and SPAC1L lost L1CAM protein and mRNA by treatment with demethylating agents or knock-down of the DNA-methyltransferase-1 (DNMT1). Concomitantly, several miRNAs were up-regulated. Using miRNA profiling, luciferase reporter assays and mutagenesis, we identified miR-34a as a putative binder to the L1CAM-3’UTR. Overexpression of miR-34a in HEC1B cells blocked L1CAM expression and inhibited cell migration. In ECC1 cells (wildtype p53) the activation of p53 caused miR-34a up-regulation and loss of L1CAM expression that was miR-34a dependent. We observed an inverse correlation between L1CAM and miR-34a levels in EC cell lines. In primary tumor sections areas expressing high amounts of L1CAM had less miR-34a expression than those with low L1CAM levels. Our data suggest that miR-34a can regulate L1CAM expression by targeting L1CAM mRNA for degradation. These findings shed new light on the complex regulation of L1CAM in human tumors.


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