miR-200b 和癌症/睾丸抗原 CAGE 形成反馈回路，调节癌细胞系对微管靶向药物的侵袭、致瘤和血管生成反应。
miR-200b and cancer/testis antigen CAGE form a feedback loop to regulate the invasion and tumorigenic and angiogenic responses of a cancer cell line to microtubule-targeting drugs.
机构信息
From the Departments of Biochemistry and.
出版信息
J Biol Chem. 2013 Dec 20;288(51):36502-18. doi: 10.1074/jbc.M113.502047. Epub 2013 Oct 30.
Cancer/testis antigen cancer-associated gene (CAGE) is known to be involved in various cellular processes, such as proliferation, cell motility, and anti-cancer drug resistance. However, the mechanism of the expression regulation of CAGE remains unknown. Target scan analysis predicted the binding of microRNA-200b (miR-200b) to CAGE promoter sequences. The expression of CAGE showed an inverse relationship with miR-200b in various cancer cell lines. miR-200b was shown to bind to the 3'-UTR of CAGE and to regulate the expression of CAGE at the transcriptional level. miR-200b also enhanced the sensitivities to microtubule-targeting drugs in vitro. miR-200b and CAGE showed opposite regulations on invasion potential and responses to microtubule-targeting drugs. Xenograft experiments showed that miR-200b had negative effects on the tumorigenic and metastatic potential of cancer cells. The effect of miR-200b on metastatic potential involved the expression regulation of CAGE by miR-200b. miR-200b decreased the tumorigenic potential of a cancer cell line resistant to microtubule-targeting drugs in a manner associated with the down-regulation of CAGE. ChIP assays showed the direct regulation of miR-200b by CAGE. CAGE enhanced the invasion potential of a cancer cell line stably expressing miR-200b. miR-200b exerted a negative regulation on tumor-induced angiogenesis. The down-regulation of CAGE led to the decreased expression of plasminogen activator inhibitor-1, a TGFβ-responsive protein involved in angiogenesis, and VEGF. CAGE mediated tumor-induced angiogenesis and was necessary for VEGF-promoted angiogenesis. Human recombinant CAGE protein displayed angiogenic potential. Thus, miR-200b and CAGE form a feedback regulatory loop and regulate the response to microtubule-targeting drugs, as well as the invasion, tumorigenic potential, and angiogenic potential.
癌症/睾丸抗原相关基因 (CAGE) 已知参与多种细胞过程，如增殖、细胞迁移和抗癌药物耐药性。然而，CAGE 的表达调控机制尚不清楚。靶扫描分析预测 microRNA-200b (miR-200b) 与 CAGE 启动子序列结合。在各种癌细胞系中，CAGE 的表达与 miR-200b 呈负相关。miR-200b 被证明与 CAGE 的 3'-UTR 结合，并在转录水平调节 CAGE 的表达。miR-200b 还增强了体外对微管靶向药物的敏感性。miR-200b 和 CAGE 对侵袭潜力和对微管靶向药物的反应表现出相反的调节作用。异种移植实验表明，miR-200b 对癌细胞的致瘤和转移潜力具有负向作用。miR-200b 对转移潜力的影响涉及 miR-200b 对 CAGE 的表达调控。miR-200b 通过下调 CAGE 降低了对微管靶向药物耐药的癌细胞系的致瘤潜力。ChIP 实验表明 miR-200b 受 CAGE 的直接调控。CAGE 增强了稳定表达 miR-200b 的癌细胞系的侵袭潜力。miR-200b 对肿瘤诱导的血管生成具有负调节作用。CAGE 的下调导致参与血管生成的 TGFβ 反应蛋白纤溶酶原激活物抑制剂-1 和 VEGF 的表达减少。CAGE 介导肿瘤诱导的血管生成，是 VEGF 促进血管生成所必需的。人重组 CAGE 蛋白显示出血管生成潜力。因此，miR-200b 和 CAGE 形成一个反馈调节环，调节对微管靶向药物的反应以及侵袭、致瘤潜力和血管生成潜力。
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