Proteomics Identified Overexpression of SET Oncogene Product and Possible Therapeutic Utility of Protein Phosphatase 2A in Alveolar Soft Part Sarcoma

Alveolar
soft part sarcoma (ASPS) is an exceedingly rare sarcoma
refractory to standard chemotherapy. Although several molecular targeting
drugs have been applied for ASPS, their clinical significance has
not yet been established, and novel therapeutic strategies have long
been required. The aim of this study was to identify proteins aberrantly
regulated in ASPS and to clarify their clinical significance. Protein
expression profiling of tumor and nontumor tissues from 12 ASPS patients
was performed by 2-D difference gel electrophoresis and mass spectrometry.
We found that the expression of 145 proteins differed significantly.
Among them, further investigation was focused on the SET protein,
which has multifunctional roles in cancers. Immunohistochemistry confirmed
overexpression of SET in all 15 ASPS cases examined. Gene silencing
of SET significantly decreased cell proliferation, invasion, and migration
against a background of induced apoptosis. SET is known to be an inhibitor
of phosphatase 2A (PP2A), which functions as a tumor suppressor by
inhibiting the signal transduction pathway and inducing apoptosis.
We found that a PP2A activator, FYN720, decreased cell proliferation
through apoptosis. Together, our findings may suggest the possible
contribution of SET to the tumor progression and the utility of FYN720
for treatment of ASPS.