In this study, the mean IRS of these three biomolecules were not found to be different between the two stages. However, four significant associations between the IRS of the three biomolecules and some clinicopathological parameters were found by univariate analysis. Particularly, high expressions of OGA, but not those of O-GlcNAc or OGT, were found to be positively associated with the percentage of post-chemotherapeutic tumor necrosis. Consistently, the high OGA expressions were only found to be significantly associated with increased overall survival and with a longer metastasis-free period in stage IIB. In addition, by multivariate analysis, the low OGA expression was found to be an independent prognostic factor for a decrease in both overall and metastasis-free survivals of patients with osteosarcoma.
In carcinoma, elevated levels of O-GlcNAc and high degrees of OGT expression, whilst decreased expression of OGA, are demonstrated in cancerous tissues of pancreas, 42 whereas only the O-GlcNAc levels and the OGT expressions are reported to be increased in lung, prostate, breast, colon and gall bladder cancers. 17, 20, 21, 24, 26, 43 However, from our recent study of O-GlcNAcylation in oral cancer, the O-GlcNAc levels have not been found to be significantly enhanced upon increased histopathologic severities of oral squamous cell carcinoma, nor have the OGT or the OGA expressions. 44 Consistent with these findings, the O-GlcNAc levels, the OGT or the OGA expressions were not found to be different between the two distinct clinical severities of osteosarcoma. Therefore, involvement of O-GlcNAcylation along with OGT and OGA expressions in the pathogenesis of osteosarcoma still requires further investigations.
By univariate analysis, the present study showed that high degrees of OGA expression, but not those of O-GlcNAc or OGT, were found to be correlated with increased overall survival with osteosarcoma. Moreover, high OGA expressions were found to be associated with increased metastasis-free survival in patients with stage IIB. These findings are consistent with the results of a previous retrospective study 45 in liver cancer that showed high OGA expressions in patients with hepatocellular carcinoma, who exhibited 3-year cumulative recurrence-free survival longer than those with low OGA expressions, implying that OGA expression in the specimens might be useful as a prognostic indicator of tumor-free survival in both hepatocellular carcinoma and osteosarcoma.
By multivariate analysis, OGT overexpression was found to be associated with prostate cancer progression and recurrence, and high O-GlcNAc levels were found to be an independent prognostic factor for poor survival. 24, 27 Increased O-GlcNAcylation levels were also associated with poor survival in patients with cholangiocarcinoma. 26 The O-GlcNAc levels and the OGT expressions were up-regulated in breast cancer cells, in which these two biomolecules appeared to contribute to tumor cell growth and invasion. 12, 21 In lung cancer, high OGT expressions were associated with poor survival of patients and with short recurrence-free survival. 17 In contrast to these findings from various types of carcinoma, our study using multivariate analysis instead demonstrated that OGA expression in osteosarcoma specimens is an independent prognostic indicator. This discrepancy may be due to different origins of tumor cells.
Several studies have shown that the histological response to pre-surgical chemotherapy, as a standard intervention for patients with osteosarcoma, is one of the most important predictors for clinical outcomes and prognosis of osteosarcoma. 46, 47 By comparison with poor responders, good responders have significantly higher overall and disease-free survival rates. In agreement with those studies, our data showed that a good chemotherapeutic response with the percentages of tumor necrosis ≥ 90 was found to be a significant positive predictor in both overall survival of all patients with osteosarcoma and metastasis-free survival in patients with stage IIB. In addition, high OGA expressions in osteosarcoma specimens were positively correlated with the good chemotherapeutic response with the percentages of tumor necrosis ≥ 90. Consequently, it is suggested by this study that both OGA expression, as a molecular marker, and the good chemotherapeutic response, as a clinical indicator, are useful for prognosis of patients with osteosarcoma. Consistently, inhibition of OGA expressions by treatment with Thiamet-G remarkably enhanced cancer cell migration and invasion in lung, colon, thyroid and ovarian cancers, 19, 48, 49 which may likely decrease a patients’ survival rate.