Abstract
Chemoresistance is a major hindrance to successful treatment of osteosarcoma (OS). Pleiotrophin (PTN), a neurotrophic growth factor, has been linked to the malignant characteristics of various cancer types. We retrospectively examined the correlation between PTN expression and chemoresistance in OS in a cohort of 133 OS patients. Immunohistochemistry revealed that PTN expression correlated with the necrosis rate and local OS recurrence. In a prognostic analysis, high PTN expression was associated with poor overall and disease-free survival, and was an independent adverse prognostic factor for disease-free survival. In doxorubicin-treated OS cells, PTN knockdown enhanced cellular chemosensitivity, increased the apoptosis rate and inhibited clone formation, while PTN overexpression had the opposite effects. In a xenograft model, PTN knockdown and overexpression respectively enhanced and reduced cellular sensitivity to doxorubicin. PTN upregulated anaplastic lymphoma kinase (ALK), p-Glycogen Synthase Kinase (GSK)3β, β-catenin and multidrug resistance protein 1/P-glycoprotein (MDR1/P-gp). In rescue assays with the β-catenin inhibitor XAV939 and the MDR1/P-gp inhibitor verapamil, PTN promoted chemoresistance to doxorubicin in OS cells by activating ALK/GSK3β/β-catenin signaling, thereby upregulating MDR1/P-gp. Therefore, PTN could be used as a biomarker predicting chemotherapeutic responses, and downregulating PTN could be a promising therapeutic strategy to prevent chemoresistance in OS patients.
Highlights
Osteosarcoma (OS) is the most common solid bone malignancy and the second leading cause of cancer-related death in children and adolescents
PTN was mainly detected in the cytoplasm of OS cells, and receiver operating characteristic (ROC) curve analysis indicated that the cutoff value of the immunoreactive score (IRS) was 5 (Figure 1B)
Kaplan-Meier survival analysis indicated that high PTN expression correlated strongly with worse overall survival (p=0.0018, Figure 1C) and disease-free survival (DFS) in OS patients (p=0.0014, Figure 1D)
Summary
Osteosarcoma (OS) is the most common solid bone malignancy and the second leading cause of cancer-related death in children and adolescents. Due to the implementation of multi-agent neoadjuvant and adjuvant chemotherapy in the 1970s, the 5-year survival rate of patients with OS has dramatically increased from approximately 10% to 70% [2]. This encouraging breakthrough has not been completely translated into improved clinical outcomes in OS patients, largely due to chemoresistance during treatment [3]. There is an urgent need to elucidate the molecular pathways underlying OS chemoresistance and to identify biomarkers that not www.impactjournals.com/oncotarget only predict individual chemotherapy responses, and can be effectively targeted to overcome chemoresistance
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