Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production.
Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production.
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DOI：
10.18632/oncotarget.1561
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发表时间：
2014-05-30
期刊：
影响因子：
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通讯作者：
Nishio K
中科院分区：
文献类型：
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作者：
Togashi Y;Arao T;Kato H;Matsumoto K;Terashima M;Hayashi H;de Velasco MA;Fujita Y;Kimura H;Yasuda T;Shiozaki H;Nishio K
染色体11 q13区带似乎是人类癌症（包括食管鳞状细胞癌（ESCC））中最常扩增的病变之一。口腔癌过表达基因1（oral cancer overexpressed 1，ORAOV 1）已在该区域内被鉴定，但其在人类ESCC中的详细生物学功能仍不清楚。在我们的III期ESCC临床样本中，在94例病例中的49例（53%）中观察到了ORAOV 1扩增。ORAOV 1扩增与低分化组织学和位于食管上段或中段的肿瘤显著相关。具有ORAOV 1扩增的患者倾向于具有较短的生存期，尽管差异不显著。为了研究ORAOV 1的功能，我们建立了过表达ORAOV 1的ESCC细胞系，与体外对照相比，该细胞系表现出细胞增殖和集落形成增加。在体内，ORAOV 1过表达的细胞表现出显着增加的致瘤性和显着更大的肿瘤体积和较差的分化比对照。肽质量指纹技术表明，ORAOV 1结合吡咯啉-5-羧酸还原酶（PYCR），这是与脯氨酸代谢和活性氧（ROS）的生产。然后，ORAOV 1过表达的细胞系对应激处理具有抗性，这被PYCR敲低所消除。此外，ORAOV 1过表达的细胞系具有较高的细胞内脯氨酸浓度和较低的ROS水平。我们的研究结果表明，ORAOV 1基因在ESCC中频繁扩增，增强致瘤性和肿瘤生长，并通过脯氨酸代谢和ROS产生与低分化肿瘤组织学相关。ORAOV 1可能成为食管鳞癌治疗的新靶点。
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.