Coordinated oncogenic transformation and inhibition of host immune responses by the PAX3-FKHR fusion oncoprotein.
Tumors have evolved elaborate mechanisms for evading immune detection, such as production of immunoinhibitory cytokines and down-regulation of major histocompatibility complex (MHC) expression. We have studied PAX3-FKHR as an example of an oncogenic fusion protein associated with an aggressive metastatic cancer. We show that PAX3-FKHR alters expression of genes that are normally regulated by Janus kinase/signal transducer and activator of transcription (STAT) signaling pathways. This occurs as a result of a specific interaction between PAX3-FKHR and the STAT3 transcription factor, which results in a dramatic reduction in tumor MHC expression, and an alteration in local cytokine concentrations to inhibit surrounding inflammatory cells and immune detection. Collectively, these data show that an oncogenic transcription factor can promote tumor growth and tissue invasion while inhibiting local inflammatory and immune responses. This is the first time that an immunomodulatory role has been described for an oncogenic fusion protein.
Nabarro
Stephen
S
Unit of Molecular Haematology and Cancer Biology, Institute of Child Health, London WC1N 1EH, England, UK.
Himoudi
Nourredine
N
Papanastasiou
Antigoni
A
Gilmour
Kimberly
K
Gibson
Sian
S
Sebire
Neil
N
Thrasher
Adrian
A
Blundell
Michael P
MP
Hubank
Mike
M
Canderan
Glenda
G
Anderson
John
J
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D051761:Paired Box Transcription Factors / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
D018836:Inflammation Mediators; D015514:Oncogene Proteins, Fusion; C471563:PAX3-FOXO1A fusion protein, human; D051761:Paired Box Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human