Metastatic progression is the major cause of death in
osteosarcoma, the most common bone
malignancy in children and young adults. However, prognostic
biomarkers and efficacious targeted treatments for metastatic disease remain lacking. Using an immunoproteomic approach, we discovered that
autoantibodies against the cell-cycle
kinase inhibitor p27 (KIP1, CDKN1B) were elevated in plasma of high-risk
osteosarcoma patients. Using a large cohort of serum samples from
osteosarcoma patients (n = 233), we validated that a higher level of the p27
autoantibody significantly correlated with poor overall and event-free survival (P < 0.05). Immunohistochemical analysis also showed that p27 was mislocalized to the cytoplasm in the majority of
osteosarcoma cases and in highly metastatic
osteosarcoma cell lines. We demonstrated that ectopic expression of cytoplasmic p27 promoted migration and invasion of
osteosarcoma cells, whereas
shRNA-mediated gene silencing suppressed these effects. In addition, mutations at the p27 phosphorylation sites S10 or T198, but not T157, abolished the migratory and invasive phenotypes. Furthermore, the development of pulmonary
metastases increased in mice injected with cells expressing cytoplasmic p27 compared with an empty vector control. Collectively, our findings support further investigation of p27 as a potential prognostic
biomarker and therapeutic target in
osteosarcoma cases exhibiting aberrant p27 subcellular localization.
Cancer Res; 76(13); 4002-11. ©2016 AACR.