title: p27 Is a Candidate Prognostic Biomarker and Metastatic Promoter in Osteosarcoma.
abstract: 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.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, Texas. Texas Children's Hematology and Oncology Centers, Texas Children's Hospital, Houston, Texas.
authors.forename: Yiting
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Texas Children's Hematology and Oncology Centers, Texas Children's Hospital, Houston, Texas.
authors.forename: Manjula
authors.initials: M
authors.lastname: Nakka
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Kelly
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, Texas. Texas Children's Hematology and Oncology Centers, Texas Children's Hospital, Houston, Texas. Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas.
authors.forename: Ching C
authors.initials: CC
authors.lastname: Lau
authors.affiliation: Children's Oncology Group, Monrovia, California. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Krailo
authors.affiliation: Children's Oncology Group, Monrovia, California. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Barkauskas
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas.
authors.forename: John M
authors.initials: JM
authors.lastname: Hicks
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas. Dan L. Duncan Cancer Center Baylor College of Medicine, Houston, Texas. Texas Children's Hematology and Oncology Centers, Texas Children's Hospital, Houston, Texas. Program of Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas. ctman@txch.org.
authors.forename: Tsz-Kwong
authors.initials: TK
authors.lastname: Man
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D002465:Cell Movement; D049109:Cell Proliferation; D002648:Child; D015331:Cohort Studies; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27