Abstract
Several studies have demonstrated a role of O-GlcNAcylation (O-GlcNAc) in tumorigenesis of various carcinomas by modification of tumor-associated proteins. However, its implication in the pathogenesis of osteosarcoma remains unclear. This study aimed to investigate the levels of O-GlcNAc and the expressions of O-linked N-acetylglucosamine transferase (OGT) and O-GlcNAcase (OGA) in human osteosarcoma tissues, by using immunohistochemistry; and to find correlations between the levels or expressions and several clinicopathologic parameters. There were 109 first diagnosed osteosarcoma patients, including Enneking stage IIB (n=70) and III (n=39). Correlations between the immunoreactive score (IRS) and clinicopathologic parameters, overall survival, and metastasis-free survival were evaluated. A positive correlation was found between the IRS of OGA and the percentage of postchemotherapeutic tumor necrosis (r=0.308; P=0.017). Univariate analysis revealed significantly lower OGA IRS in metastatic patients (P=0.020) and poor chemotherapeutic-responder patients (P=0.001). By multivariate analysis, presence of tumor metastasis (P=0.002) and lower OGA IRS (P=0.004) was significantly associated with shorter overall survival. Subgroup analysis in stage IIB osteosarcoma (n=70) demonstrated that male sex (P=0.019), presence of tumor recurrence (P=0.026), poor chemotherapeutic responder (P=0.022), and lower OGA IRS (P=0.019) were significantly correlated with short metastasis-free survival. But, lower OGA IRS was the only independent predictor for short metastasis-free survival (P=0.006). Our findings suggested that O-GlcNAc pathway, especially OGA, may involve in pathogenesis and aggressiveness of osteosarcoma. Low level of OGA expression may be used as a poor prognostic indicator.
Highlights
Several studies have demonstrated a role of O-GlcNAcylation (O-GlcNAc) in tumorigenesis of various carcinomas by modification of tumor-associated proteins
Aberrations of O-GlcNAc are associated with the pathogenesis of many human diseases, including diabetes, neurodegenerative diseases and cancers. 6, 8–11 With respect to cancer pathogenesis and progression, several key players, such as p53, c-Myc, Forkhead box M1 (FoxM1) etc., have been shown to be modified via the O-GlcNAc pathway. 12–15 Recently, several cancer studies have reported that elevated O-GlcNAc is associated with tumorigenesis and cancer cell metastasis. 12, 16–25 several previous studies have shown that hyper-O-GlcNAc and overexpression of O-linked N-acetylglucosamine transferase (OGT) were associated with worse clinicopathological outcomes in various cancers. 17, 21, 26, 27
A moderate and positive correlation was found between the imunoreactive score (IRS) of OGA expression and the percentage of postchemotherapeutic tumor necrosis in 60 cases (r = 0.308, P = 0.017; Figure 2), whereas the O-GlcNAc IRS or the OGT IRS was not found to be correlated with the percentage of post-chemotherapeutic tumor necrosis
Summary
Several studies have demonstrated a role of O-GlcNAcylation (O-GlcNAc) in tumorigenesis of various carcinomas by modification of tumor-associated proteins. O-GlcNAcylation (O-GlcNAc) is a post-translational modification of proteins associated with regulation of various protein functions by an addition of N-acetylglucosamine (GlcNAc) to the hydroxyl group of serine or threonine residues of the target proteins This modification is a dynamic and reversible process, strictly regulated by two important enzymes, O-linked N-acetylglucosamine transferase (OGT) and O-GlcNAcase (OGA), which add and remove the GlcNAc moieties, respectively. Based on our previous study, 37 it was found that O-GlcNAc levels and OGT expression were increased in primary cancer cells isolated from patients with osteosarcoma in association with metastasis and poor response to chemotherapy. The expressions of OGT and OGA, and the levels of O-GlcNAc were, examined in 109 bone specimens, histopathologically diagnosed as osteosarcoma using immunohistochemistry, and the correlations were determined between the O-GlcNAc profiles and several clinicopathological characteristics at the time of diagnosis as well as patients’ treatment outcomes
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