Oncotarget

Research Papers:

C/EBPβ-1 promotes transformation and chemoresistance in Ewing sarcoma cells

Jamie D. Gardiner, Lisa M. Abegglen, Xiaomeng Huang, Bryce E. Carter, Elizabeth A. Schackmann, Marcus Stucki, Christian N. Paxton, R. Lor Randall, James F. Amatruda, Angelica R. Putnam, Heinrich Kovar, Stephen L. Lessnick and Joshua D. Schiffman _

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Oncotarget. 2017; 8:26013-26026. https://doi.org/10.18632/oncotarget.14847

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Abstract

Jamie D. Gardiner1,*, Lisa M. Abegglen1,*, Xiaomeng Huang1, Bryce E. Carter2, Elizabeth A. Schackmann2, Marcus Stucki1, Christian N. Paxton3, R. Lor Randall4, James F. Amatruda5, Angelica R. Putnam6, Heinrich Kovar7, Stephen L. Lessnick8, Joshua D. Schiffman1

1Department of Pediatrics, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

2School of Medicine, University of Utah, Salt Lake City, UT, USA

3ARUP Institute for Clinical and Experimental Pathology®, Salt Lake City, UT, USA

4Department of Orthopaedic Surgery, Sarcoma Services, University of Utah, Salt Lake City, UT, USA

5Department of Pediatrics, Internal Medicine and Molecular Biology, University of Texas Southwestern, Dallas, TX, USA

6Department of Pathology, University of Utah, Salt Lake City, UT, USA

7Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria

8Center for Childhood Cancer and Blood Disorders, Nationwide Children’s Hospital, and the Division of Pediatric Heme/Onc/BMT, The Ohio State University, Columbus, OH, USA

*These authors contributed equally to this work

Correspondence to:

Joshua D. Schiffman, email: joshua.schiffman@hci.utah.edu

Keywords: Ewing sarcoma, C/EBPβ, ALDH1A1, chemoresistance, biomarker

Received: July 18, 2016     Accepted: January 16, 2017     Published: January 27, 2017

ABSTRACT

CEBPB copy number gain in Ewing sarcoma was previously shown to be associated with worse clinical outcome compared to tumors with normal CEBPB copy number, although the mechanism was not characterized. We employed gene knockdown and rescue assays to explore the consequences of altered CEBPB gene expression in Ewing sarcoma cell lines. Knockdown of EWS-FLI1 expression led to a decrease in expression of all three C/EBPβ isoforms while re-expression of EWS-FLI1 rescued C/EBPβ expression. Overexpression of C/EBPβ-1, the largest of the three C/EBPβ isoforms, led to a significant increase in colony formation when cells were grown in soft agar compared to empty vector transduced cells. In addition, depletion of C/EBPβ decreased colony formation, and re-expression of either C/EBPβ-1 or C/EBPβ-2 rescued the phenotype. We identified the cancer stem cell marker ALDH1A1 as a target of C/EBPβ in Ewing sarcoma. Furthermore, increased expression of C/EBPβ led to resistance to chemotherapeutic agents. In summary, we have identified CEBPB as an oncogene in Ewing sarcoma. Overexpression of C/EBPβ-1 increases transformation, upregulates expression of the cancer stem cell marker ALDH1A1, and leads to chemoresistance.


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