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Summary: Oral squamous cell carcinoma (OSCC) is the major cancer of head and neck with increasing incidence and mortality in Taiwan. We investigate hnRNP K, TP and FLIP expression and assess the prognostic and therapeutic potential of these markers in oral squamous cell carcinoma (OSCC). We analyzed hnRNP K, TP, and FLIP expression in 110 OSCC patients by immunohistochemistry. Statistical analyses were applied to correlate nuclear and cytoplasmic hnRNP K with elevated TP and FLIP, and to determine the associations of these three markers with clinicopathological manifestations, and assess their prognostic and therapeutic significance. The therapeutic implication of elevated TP was determined by measuring the sensitivity of OSCC cells to the TP-targeting drug, 5-fluoro-5′-deoxyuridine (5′-DFUR). We found that each of these proteins was overexpressed in OSCC tumors. Nuclear hnRNP K and cytoplasmic hnRNP K were strongly associated with TP (r 2 =0.344, P =0.0004) and FLIP (r 2 =0.201, P =0.035), respectively. High hnRNP K and TP levels were associated with clinicopathological parameters predictive of poorer treatment outcome. Multivariate analyses indicated that cytoplasmic hnRNP K and TP are independent predictors of overall survival (P =0.022 and 0.009, respectively) and disease-free survival (P =0.012 and 0.005, respectively). OSCC cells expressing high levels of TP were more sensitive to treatment with 5′-DFUR. Elevated cytoplasmic hnRNP K and TP overexpression are associated with poorer survival in OSCC patients. In vitro experiments suggest that OSCC tumors with high levels of TP are more sensitive to 5′-DFUR treatment. Thus, cytoplasmic hnRNP K and TP may be potential prognostic and therapeutic markers for OSCC. [ABSTRACT FROM AUTHOR]