Abstract
Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC). The oral cancer overexpressed 1 (ORAOV1) gene has been identified within this region, but its detailed biological function in human ESCC remains largely unclear. In our clinical samples of stage III ESCC, ORAOV1 amplification was observed in 49 of 94 cases (53%). ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus. Patients with ORAOV1 amplification tended to have a shorter survival period, although the difference was not significant. To investigate the function of ORAOV1, we created ORAOV1--overexpressed ESCC cell lines that exhibited increased cellular proliferation and colony formation, compared with in vitro controls. In vivo, ORAOV1-overexpressed cells exhibited a significantly increased tumorigenicity and a significantly larger tumor volume and poorer differentiation than controls. The peptide mass fingerprinting technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism and reactive oxygen species (ROS) production. Then, ORAOV1-overexpressed cell lines were resistant to stress treatment, which was cancelled by PYCR-knockdown. In addition, the ORAOV1-overexpressed cell line had a higher intracellular proline concentration and a lower ROS level. Our findings indicate that the ORAOV1 gene is frequently amplified in ESCC, enhances tumorigenicity and tumor growth, and is associated with a poorly differentiated tumor histology via proline metabolism and ROS production. ORAOV1 could be a novel target for the treatment of ESCC.
Highlights
Among the malignancies of the gastrointestinal tract, esophageal cancer is associated with a poor prognosis despite improvements in surgical techniques, chemotherapy, and chemoradiotherapy [1, 2]
A very high oral cancer overexpressed 1 (ORAOV1) mRNA expression level was observed in several esophageal squamous cell cancer (ESCC) cell lines, whereas the levels in lung cancer, including squamous cell cancer and gastric cancer, were not so high (Figure 1B)
KYSE70-pQCLINORAOV1 cells produced poorly differentiated tumors (Figure 5C). These results indicate that the ORAOV1 gene is involved in tumorigenesis and tumor growth, as seen in vitro, and is associated with a poorly differentiated histology
Summary
Among the malignancies of the gastrointestinal tract, esophageal cancer is associated with a poor prognosis despite improvements in surgical techniques, chemotherapy, and chemoradiotherapy [1, 2]. Neoadjuvant chemo-radiation followed by surgery remains the standard of care for operable disease. Definitive chemoradiation can be considered for locally advanced tumors, while platinum-based combination chemotherapy is preferable in a first-line metastatic setting. HER2-, EGFR-, and VEGF-targeted agents have been extensively investigated as single agents or in combination with chemotherapy. Several new targets, including mTOR- and MET-targeted agents, are being explored [2]. None of the molecular-targeted www.impactjournals.com/oncotarget therapies developed to date have enabled a demonstrated improvement in the survival of patients with esophageal cancer. The search for novel targeted molecules must be continued
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