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EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1

Panneerselvam Jayabal, Peter J. Houghton, Yuzuru Shiio
doi: https://doi.org/10.1101/195693
Panneerselvam Jayabal
1Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
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Peter J. Houghton
1Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
2Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
3Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
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Yuzuru Shiio
1Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
2Cancer Therapy and Research Center, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
4Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA
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  • For correspondence: shiio@uthscsa.edu
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Abstract

Ewing sarcoma is an aggressive cancer of bone and soft tissue in children with poor prognosis. It is characterized by the chromosomal translocation between EWS and an Ets family transcription factor, most commonly FLI-1. EWS-FLI-1 fusion accounts for 85% of Ewing sarcoma cases. EWS-FLI-1 regulates the expression of a number of genes important for sarcomagenesis, can transform NIH3T3 and C3H10T1/2 cells, and is necessary for proliferation and tumorigenicity of Ewing sarcoma cells, suggesting that EWS-FLI-1 is the causative oncoprotein.

Here we report that EWS-FLI-1 induces the expression of pappalysin-1 (PAPPA), a cell surface protease that degrades IGF binding proteins (IGFBPs) and increases the bioavailability of IGF. EWS-FLI-1 binds to the pappalysin-1 gene promoter and stimulates the expression of pappalysin-1, leading to degradation of IGFBPs and enhanced IGF signaling. Silencing of pappalysin-1 strongly inhibited anchorage-dependent and anchorage-independent growth as well as xenograft tumorigenicity of Ewing sarcoma cells. These results suggest that EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1, which emerged as a novel target to inhibit IGF signaling in Ewing sarcoma.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 28, 2017.
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EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1
Panneerselvam Jayabal, Peter J. Houghton, Yuzuru Shiio
bioRxiv 195693; doi: https://doi.org/10.1101/195693
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EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1
Panneerselvam Jayabal, Peter J. Houghton, Yuzuru Shiio
bioRxiv 195693; doi: https://doi.org/10.1101/195693

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