O3–053 - ORAOV1 is Amplified in Esophageal Squamous Cell Cancer and Related to Tumor Growth and Poorly Differentiated Tumor

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Background: Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer including esophageal squamous cell cancer (ESCC). Oral cancer overexpressed 1 (ORAOV1) was identified within this region, which is presumably a candidate treatment target in oral squamous cell cancer. Although recent study has demonstrated that yeast orthologue of ORAOV1 is related to reactive oxygen species (ROS), its detail biological function in human ESCC remains unclear. Methods: To investigate the function, we made ORAOV1 overexpressed ESCC cell lines using stable viral transfection technique. In order to search for the binding protein with ORAOV1, peptide mass fingerprinting and co-immunoprecipitation technique were used. In addition, ORAOV1 amplification was evaluated using the copy number assay in 94 clinical samples of stage III ESCC and the association with clinical characteristics was analyzed. Results: ORAOV1 overexpressed ESCC cell lines showed increased cellular proliferation and colony formation compared with control cells in vitro. In vivo, ORAOV1 overexpressed cells exhibited a significantly larger tumor volume and poorlier differentiated tumor than control cells. Peptide mass fingerprinting and co-immunoprecipitation technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase, which is associated with proline metabolism and ROS production. Then, ORAOV1 overexpressed cells produced lower ROS level than control cells and were resistant to stress treatment. In clinical samples, ORAOV1 amplification of more than 4 copies was observed in 49 cases (53%). ORAOV1 amplification was significantly associated with poorly differentiated and upper or middle located tumor (P = 0.033 and 0.012, respectively). Patients with ORAOV1 amplification tended to have shorter (but not significant) survival than non-amplification patients (median overall survival, 21.6 vs 33.7 months, P = 0.16). Conclusion: ORAOV1 is frequently amplified in ESCC, enhances tumor growth, and is associated with poorly differentiated tumor via proline metabolism and ROS production. Our findings indicate that ORAOV1 can become a novel treatment target in ESCC.