Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma.
Aberrant DNA Methylation as a Biomarker and a Therapeutic Target of Cholangiocarcinoma.
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DOI：
10.3390/ijms18061111
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发表时间：
2017-05-23
影响因子：
5.6
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Nakaoka T;Saito Y;Saito H
胆管癌是一种发生于肝内胆管和胆总管远端乏特壶腹之间的上皮恶性肿瘤。目前的化疗方案对胆管癌的疗效有限，患者预后差。异常的DNA甲基化和组蛋白修饰诱导肿瘤抑制基因沉默和染色体不稳定性。研究表明，肿瘤抑制基因和微小RNA（miRNAs），包括MLH 1、p14、p16、死亡相关蛋白激酶（DAPK）、miR-370和miR-376 c，在胆管癌中经常发生甲基化。这些抑癌基因和miRNAs的沉默在胆管癌的发生和发展中起着关键作用。此外，最近的研究表明，DNA甲基化抑制剂诱导内源性逆转录病毒的表达，并通过抗病毒免疫反应发挥抗肿瘤作用。抑癌基因和miRNAs的异常甲基化可能是胆管癌诊断和治疗的一个有力的生物标志物。用DNA甲基化抑制剂的表观遗传疗法通过重新激活肿瘤抑制基因和miRNA以及诱导抗病毒免疫应答而为胆管癌的治疗带来了相当大的希望。
Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, death-associated protein kinase (DAPK), miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for the diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors holds considerable promise for the treatment of cholangiocarcinoma through the reactivation of tumor suppressor genes and miRNAs as well as the induction of an anti-viral immune response.