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Low abundance of TFPI-2 by both promoter methylation and miR-27a-3p regulation is linked with poor clinical outcome in gastric cancer.
低丰度的 TFPI-2 启动子甲基化和 miR-27a-3p 调控与胃癌的不良临床预后有关。
- 影响因子：1.49
- DOI：10.1002/jgm.3166
- 作者列表："Geng G","Liu X","Xu A","Lu Z","Chen K","He J","Qi D","Yuan X
- 发表时间：2020-01-26
Abstract
BACKGROUND:The tumor suppressor role of tissue factor pathway inhibitor 2 (TFPI-2) has been reported in various tumors. This study aimed to improve the understanding of the oncogenic properties of TFPI-2 in gastric cancer. METHODS:Relative expression of TFPI-2 was determined by real-time polymerase chain reaction (PCR) and Western blot, respectively. Cell viability was measured with Cell Counting Kit-8 assay and proliferation was evaluated by colony formation assay. Cell apoptosis was assessed with caspase-3 activity kit and invasion was evaluated by transwell chamber assay. The methylation level of TFPI-2 promoter was assayed by methylation-specific PCR. The regulatory effect of miR-27a-3p on TFPI-2 was analyzed with luciferase reporter assay. The direct association between miR-27a-3p and TFPI-2 was shown by biotin-labelling pulldown. RESULTS:TFPI-2 was down-regulated in gastric cancer, which associated with unfavorable prognosis clinically. Ectopic introduction of TFPI-2 greatly compromised cell viability, colony formation, and invasive capacity and induced cell apoptosis simultaneously. The promoter region of TFPI-2 was extensively methylated in gastric cancer tissues in comparison with normal tissues, suggesting the epigenetic inhibition of TFPI-2 expression. We further identified that TFPI-2 functioned as sponge RNA against miR-27a-3p. Most importantly, miR-27a-3p-specific inhibitor significantly exerted tumor suppressor function akin to TFPI-2 itself, and the anti-tumoral activities were completely abolished by TFPI-2 knockdown. CONCLUSIONS:We discovered that the epigenetically suppressed TFPI-2 compromised sponging effects on miR-27a-3p in gastric cancer, which consequently and mechanistically contributed to tumor biology of gastric cancer.
摘要
背景: 组织因子途径抑制物 2 (TFPI-2) 的肿瘤抑制作用在多种肿瘤中已有报道。本研究旨在提高对胃癌 TFPI-2 致癌特性的认识。 方法: 采用实时荧光定量聚合酶链反应 (PCR) 和免疫印迹法 (Western blot) 检测 TFPI-2 的相对表达量。细胞活力用细胞计数试剂盒-8 法测定，增殖用集落形成法评价。用 caspase-3 活性试剂盒评估细胞凋亡，用 transwell 小室试验评估侵袭。用甲基化特异性 PCR 检测 TFPI-2 启动子甲基化水平。用荧光素酶报告基因技术分析 miR-27a-3p 对 TFPI-2 的调节作用。通过生物素标记下拉显示 miR-27a-3p 与 TFPI-2 之间的直接关联。 结果: TFPI-2 在胃癌中表达下调，临床预后不良。异位引入 TFPI-2 极大地损害了细胞活力、集落形成和侵袭能力，并同时诱导细胞凋亡。与正常组织相比，TFPI-2 的启动子区在胃癌组织中广泛甲基化，提示表观遗传抑制了 TFPI-2 的表达。我们进一步鉴定 TFPI-2 作为海绵 RNA 作用于 miR-27a-3p。最重要的是，miR-27a-3p-specific 抑制剂显著发挥肿瘤抑制功能，类似于 TFPI-2 本身，并且通过 TFPI-2 敲除完全消除了抗肿瘤活性。 结论: 我们发现表观遗传学抑制了 TFPI-2 对胃癌 miR-27a-3p 的海绵效应，从而在机制上促进了胃癌的肿瘤生物学。
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