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TFF1 targeting therapeutic strategy for dissemination of gastric cancer

TFF1靶向治疗胃癌扩散的策略

基本信息

批准号：
23791548
负责人：
NAKAMURA Jun
金额：
$ 2.16万
依托单位：
Saga University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791548/
关键词：
TFF1 胃癌低酸素 DNAメチル化浸潤能

项目摘要

Trefoil factor 1 (TFF1) is considered to be a tumor suppressor gene in gastric cancer. However, the role of TFF1 expression and its regulation in gastric cancer patients remain unclear. The aims of this study were to clarify the clinical significance of TFF1 and to determine its regulatory mechanisms. We assessed the immunohistochemical expression of TFF1 in 182 gastric cancer patients and examined whether or not TFF1 is associated with the clinicopathological factors and patient survival. In vitro study using TFF1 knockdown gastric cancer cells evaluated the role of TFF1 in cancer invasion. Bisulfite sequencing was performed to assess DNA methylation of TFF1 in cells and resected tissues. Patients with low expression of TFF1 showed a significantly deeper invasion of the tumor than those with high expression (p=0.037). Low expression of TFF1 was also associated with a poor survival (p=0.029) in 108 patients who were treated by surgery alone. Both TFF1 expression and lymph node metastasis are independent predictive factors for disease-specific survival in a multivariate analysis. In an in vitro study, invasive power of the cells was significantly increased in the　TFF1-deficient cells compared with the control cells. Bisulfate sequencing showed that TFF1 expression is strongly dependent on DNA methylation in both gastric cancer cells and tissues. Interestingly, methylation status of two specific CpG sites, which are located close to a TATA box and hypoxia response element (HRE), determined the TFF1 expression in the resected tissues. TFF1 expression is silenced by DNA methylation and is associated with tumor invasion and a poor survival in gastric cancer patients. The expression and　or methylation status of TFF1 may, therefore, serve as a useful biomarker for predicting survival in patients with advanced gastric cancer.

三叶因子1(TFF1)被认为是胃癌的抑癌基因。然而，TFF1在胃癌患者中的表达及其调控的作用尚不清楚。本研究的目的是阐明TFF1的临床意义，并确定其调节机制。我们检测了182例胃癌组织中TFF1的免疫组织化学表达，并探讨了TFF1与临床病理因素和患者生存期的关系。利用TFF1基因敲除胃癌细胞的体外研究评价了TFF1在肿瘤侵袭中的作用。亚硫酸氢盐测序检测TFF1在细胞和切除组织中的DNA甲基化。TFF1低表达患者的肿瘤侵袭深度明显高于高表达患者(p=0.037)。在接受单纯手术治疗的108例患者中，TFF1的低表达也与生存不良有关(p=0.029)。在多因素分析中，TFF1的表达和淋巴结转移都是疾病特异性生存的独立预测因素。在体外研究中，与对照细胞相比，TFF1缺陷细胞的侵袭能力显著增加。硫酸氢测序显示TFF1在胃癌细胞和组织中的表达强烈依赖于DNA甲基化。有趣的是，位于TATA盒和缺氧反应元件(HRE)附近的两个特定CpG位点的甲基化状态决定了TFF1在切除组织中的表达。TFF1的表达被DNA甲基化抑制，并与胃癌患者的肿瘤侵袭和不良生存有关。因此，TFF1的表达和/或甲基化状态可作为预测进展期胃癌患者生存的有用生物标志物。