论文标题：PARP1 activation increases expression of modi?ed tumor suppressors and pathways underlying development of aggressive hepatoblastoma
期刊：
作者：Nikolai Timchenko et al
发表时间：2018/06/11
数字识别码：10.1038/s42003-018-0077-8
原文链接：
在近期《通讯-生物学》上发表的名为PARP1 activation increases expression of modi?ed tumor suppressors and pathways underlying development of aggressive hepatoblastoma的研究里，辛辛那提儿童医院的Nikolai Timchenko带领的团队识别了一个有潜力成为侵袭性儿童肝癌的药物靶点。
肝母细胞癌 （HBL）是最普遍的儿童肝癌，占总病例的60%到85%，在每一百万儿童里有0.5 到1.5 例，最常在三岁以下的儿童群中发病。虽然在近年内HBL的综合的生存率有所改善，仍有很多的病者要面对癌症的扩散和有侵袭性、耐药的、和手术无法切除的肿瘤。通常肝癌病者的抑癌蛋白的表达比正常人有所下降。
Timchenko带领的团队的研究研究了大量的HBL肿瘤样本，发现HBL肿瘤样本里有上升的PARP1的表达。PARP1活跃于多个和癌症有关的信号通路， 参与细胞核内染色质的再塑造，导致细胞增加对癌症药的耐药性。研究者们发现，PARP1和很多与癌症相关的基因的DNA有结合并且激化它们的表达从而推进癌症的发展。美国食品药品管理局已经批准的癌症标靶药奥拉帕尼（Olaparib）能阻止PARP1的活动和停滞癌症的发展。
Timchenko博士说：“我们的发现为PARP1抑制剂在儿童肝癌上的应用奠定了一定的基础。当然，在临床应用之前我们需要做更多的研究，包括在大小鼠模型上的实验。”
摘要：Hepatoblastoma (HBL) is a pediatric liver cancer that affects children under the age of three. Reduction of tumor suppressor proteins (TSPs) is commonly seen in liver cancer. However, in our studies we find that aggressive, chemo-resistant HBLs exhibit an elevation of TSPs. HBL patients with a classic phenotype have reduced TSP levels, but patients with aggressive HBL express elevated TSPs that undergo posttranslational modifications, eliminating their tumor suppression activities. Here we identify unique aggressive liver cancer domains (ALCDs) that are activated in aggressive HBL by PARP1-mediated chromatin remodeling leading to elevation of modified TSPs and activation of additional cancer pathways: WNT signaling and β-catenin. Inhibition of PARP1 blocks activation of ALCDs and normalizes expression of corresponding genes, therefore reducing cell proliferation. Our studies reveal PARP1 activation as a mechanism for the development of aggressive HBL, further suggesting FDA-approved PARP1 inhibitors might be used for treatment of patients with aggressive HBL.
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