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Background Glucosylceramide synthase (GCS),an enzyme responsible for ceramide glycosylation,plays an important role in multidrug resistance (MDR) in some tumors in vitro; however,its expression and clinicopathological significance in non-small cell lung cancer (NSCLC) remains unclear.Methods We evaluated GCS expression in 116 paired tumor and adjacent non-cancerous tissues and 50 frozen tissues from patients with NSCLC using immunohistochemistry and west blotting,and explored the correlation between GCS and NSCLC clinicopathological characteristics and prognosis.We observed the association between GCS and the MDR proteins P-glycoprotein (P-gp) and lung resistance-related protein (LRP) to determine the link between GCS and MDR at the histological level.Results GCS expression was significantly upregulated in NSCLC tumors compared with non-cancerous tissue.There was high GCS expression in 75/116 tumor specimens (64.7％) and 16/116 non-cancerous specimens (13.8％).High GCS expression was significantly associated with poor differentiation (P=0.01),lymph node metastasis (P=0.004),recurrence/ distant metastasis (P=0.006),and chemotherapy resistance (P=0.025).Multivariate analysis demonstrated that GCS immunopositivity was an independent risk factor for survival (P=0.018).P-gp was expressed in 80/116 tumors (69.0％) and in 12/116 non-cancerous tissue specimens (10.3％; P=0.001); LRP was expressed in 85/116 tumors (73.3％) and 19/116 non-cancerous tissue specimens (16.4％; P=0.001).Importantly,the results demonstrated that increased GCS expression in NSCLC cancer specimens correlated with increased expression of P-gp and LRP,molecules known to stimulate cancer cell MDR (r=0.612 and 0.503,P=0.01 and 0.035,respectively).Conclusion GCS upregulation might contribute to the development of NSCLC and could be a useful prognostic indicator and chemoresistance predictor for NSCLC patients.