Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer
Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer
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DOI：
10.1111/cas.14028
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发表时间：
2019-05
期刊：
影响因子：
5.7
通讯作者：
Y. Kiyozumi;Y. Baba;K. Okadome;T. Yagi;Y. Ogata;K. Eto;Y. Hiyoshi;T. Ishimoto;M. Iwatsuki;S. Iwagami;Y. Miyamoto;N. Yoshida;Masayuki Watanabe;H. Baba
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文献类型：
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作者：
Y. Kiyozumi;Y. Baba;K. Okadome;T. Yagi;Y. Ogata;K. Eto;Y. Hiyoshi;T. Ishimoto;M. Iwatsuki;S. Iwagami;Y. Miyamoto;N. Yoshida;Masayuki Watanabe;H. Baba
吲哚胺2，3-双加氧酶1（IDO 1）是产生免疫抑制代谢物的主要酶。它在肿瘤免疫学中起着重要作用，是一种潜在的基于免疫的治疗靶点。我们已经报道IDO 1蛋白表达与食管癌的不良临床结局相关。最近，有报道IDO 1的表达受IDO 1启动子甲基化的调控。因此，本研究的目的是研究IDO 1表达，IDO 1启动子甲基化和食管癌临床病理特征之间的关系。我们首先通过用5-氮杂胞苷处理细胞在体外证实了IDO 1表达水平的变化。然后，我们使用40个冷冻样本和242个福尔马林固定的石蜡包埋的食管癌患者切除样本，评估IDO 1表达水平、IDO 1启动子甲基化（亚硫酸氢盐焦磷酸测序）和临床病理特征之间的关系。我们用5-氮杂胞苷处理细胞系，所产生的低甲基化诱导了显著更高的IDO 1表达（P < .001）。在冷冻样本中，IDO 1表达水平与IDO 1启动子甲基化水平呈负相关（R =-0.47，P = .0019）。此外，IDO 1启动子低甲基化组（n = 67）的患者与IDO 1启动子高甲基化组（n = 175）相比预后较差（总生存率，P = 0.011）。我们的研究结果表明，IDO 1启动子低甲基化调节IDO 1的表达，并与食管癌患者的预后不良。
Indoleamine 2, 3‐dioxygenase 1 (IDO1) is a primary enzyme that generates immunosuppressive metabolites. It plays a major role in tumor immunology and is a potential immune‐based therapeutic target. We have reported that IDO1 protein expression was associated with an unfavorable clinical outcome in esophageal cancer. Recently, it has been reported that IDO1 expression is regulated by methylation of the IDO1 promoter. Thus, the aim of this study was to examine the relationship between IDO1 expression, IDO1 promoter methylation, and clinicopathological features in esophageal cancer. We first confirmed changes in IDO1 expression levels in vitro by treating cells with 5‐azacytidine. We then evaluated the relationship between IDO1 expression levels, IDO1 promoter methylation (bisulfite pyrosequencing), and clinicopathological features using 40 frozen samples and 242 formalin‐fixed, paraffin‐embedded samples resected from esophageal cancer patients. We treated cell lines with 5‐azacytidine, and the resulting hypomethylation induced significantly higher IDO1 expression (P < .001). In frozen samples, IDO1 expression levels correlated inversely with IDO1 promoter methylation levels (R = −0.47, P = .0019). Furthermore, patients in the IDO1 promoter hypomethylation group (n = 67) had a poor prognosis compared with those in the IDO1 promoter hypermethylation group (n = 175) (overall survival, P = .011). Our results showed that IDO1 promoter hypomethylation regulated IDO1 expression and was associated with a poor prognosis in esophageal cancer patients.