Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer.
Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0626
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发表时间：
2017-04-15
期刊：
影响因子：
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通讯作者：
Amor-Guéret M
中科院分区：
文献类型：
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作者：
Mameri H;Bièche I;Meseure D;Marangoni E;Buhagiar-Labarchède G;Nicolas A;Vacher S;Onclercq-Delic R;Rajapakse V;Varma S;Reinhold WC;Pommier Y;Amor-Guéret M
癌症治疗的主要挑战之一是确定介导治疗耐药性或敏感性的分子机制。据报道，布卢姆综合征患者的细胞中胞苷脱氨酶 (CDA) 表达下调，布卢姆综合征是一种与多种癌症的强烈易感性相关的遗传性疾病。本研究的目的是确定 CDA 缺乏是否与普通人群的肿瘤有关，并可以构成抗肿瘤药物敏感性的预测标记。我们使用 IHC、PDX、qRT-PCR 和 Western blotting 在计算机上分析了癌细胞系和肿瘤的大型数据集中以及各种癌细胞系和原发性肿瘤组织中的 CDA 表达。我们还研究了 CDA 沉默的机制，并使用计算机分析与经典细胞实验方法相结合，寻找可能特异性靶向 CDA 缺陷肿瘤细胞的分子。我们发现约 60% 的癌细胞和组织中 CDA 表达下调。我们证明 DNA 甲基化是肿瘤中 CDA 沉默的普遍机制。最后，我们表明，表观遗传治疗和抗癌药物氨基黄酮可以专门针对 CDA 缺陷的肿瘤细胞。 CDA 表达状态可识别新的癌症亚群，CDA 缺乏似乎是对抗肿瘤药物敏感性的一种新颖且相关的预测标记，为治疗癌症开辟了新的可能性。
One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to antitumor drugs. We analyzed CDA expression in silico,in large datasets for cancer cell lines and tumors and in various cancer cell lines and primary tumor tissues using IHC, PDXs, qRT-PCR, and Western blotting. We also studied the mechanism underlying CDA silencing and searched for molecules that might target specifically CDA-deficient tumor cells using in silico analysis coupled to classical cellular experimental approaches. We found that CDA expression is downregulated in about 60% of cancer cells and tissues. We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors. Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone. CDA expression status identifies new subgroups of cancers, and CDA deficiency appears to be a novel and relevant predictive marker of susceptibility to antitumor drugs, opening up new possibilities for treating cancer.