RT Journal Article
SR Electronic
T1 EWS-FLI-1 creates a cell surface microenvironment conducive to IGF signaling by inducing pappalysin-1
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 195693
DO 10.1101/195693
A1 Panneerselvam Jayabal
A1 Peter J. Houghton
A1 Yuzuru Shiio
YR 2017
UL http://biorxiv.org/content/early/2017/09/28/195693.abstract
AB 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.