Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.
Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.
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DOI：
10.1186/s12964-022-00850-2
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发表时间：
2022-03-28
期刊：
影响因子：
--
通讯作者：
Feng L
中科院分区：
文献类型：
--
作者：
Chen M;Wang W;Hu S;Tong Y;Li Y;Wei Q;Yu L;Zhu L;Zhu Y;Liu L;Ju Z;Wang X;Jin H;Feng L
肝细胞癌（HCC）是最致命的癌症之一。由于有效治疗的策略有限，晚期HCC患者的预后非常差。本研究旨在确定HCC的新见解，以制定HCC管理的新策略。在HCC细胞、异种移植模型、用WIP 1基因敲除小鼠的DEN（二乙基亚硝胺）诱导的小鼠肝癌模型和TCGA数据库中分析WIP 1（野生型p53诱导的蛋白磷酸酶1）在HCC中的作用。通过基因集富集分析、蛋白质印迹法、彗星试验和免疫荧光法评价DNA损伤。WIP 1的高表达与HCC患者的不良预后相关。WIP 1的遗传和化学抑制显著降低了HCC细胞的增殖。此外，WIP 1基因敲除可抑制DEN诱导的小鼠肝癌发生。在机械上，WIP 1抑制通过增加H2 AX磷酸化（γ H2 AX）诱导DNA损伤。因此，WIP 1和PARP的抑制通过增加DNA损伤在体外和体内诱导HCC的合成致死性。WIP 1在HCC的发展中起着致癌作用，单独靶向WIP 1依赖的DNA损伤修复或与PARP抑制相结合可能是HCC管理的合理策略。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-022-00850-2获取。
Hepatocellular carcinoma (HCC) is one of the most fatal cancers. Due to limited strategies for effective treatments, patients with advanced HCC have a very poor prognosis. This study aims to identify new insights in HCC to develop novel strategies for HCC management. The role of WIP1 (wild type p53 induced protein phosphatase1) in HCC was analyzed in HCC cells, xenograft model, DEN (Diethylnitrosamine) induced mice liver cancer model with WIP1 knockout mice, and TCGA database. DNA damage was evaluated by Gene Set Enrichment Analysis, western blotting, comet assay, and Immunofluorescence. High expression of WIP1 is associated with the poor prognosis of patients with HCC. Genetically and chemically suppression of WIP1 drastically reduced HCC cell proliferation. Besides, WIP1 knockout retarded DEN induced mice hepato-carcinogenesis. Mechanically, WIP1 inhibition induced DNA damage by increasing H2AX phosphorylation (γH2AX). Therefore, suppression of WIP1 and PARP induced synthetic lethality in HCC in vitro and in vivo by augmenting DNA damage. WIP1 plays an oncogenic effect in HCC development, and targeting WIP1-dependent DNA damage repair alone or in combination with PARP inhibition might be a reasonable strategy for HCC management. Video abstract The online version contains supplementary material available at 10.1186/s12964-022-00850-2.
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DOI：
10.1073/pnas.94.12.6048
发表时间：
1997-06-10
影响因子：
11.1
作者：
Fiscella, M;Zhang, HL;Appella, E
通讯作者：
Appella, E
影响因子：
16
作者：
Lu, XB;Bocangel, D;Donehower, LA
通讯作者：
Donehower, LA
影响因子：
6
作者：
Burdova, Kamila;Storchova, Radka;Macurek, Libor
通讯作者：
Macurek, Libor
影响因子：
--
作者：
He L;Tian DA;Li PY;He XX
通讯作者：
He XX
影响因子：
23.9
作者：
Hsu JI;Dayaram T;Tovy A;De Braekeleer E;Jeong M;Wang F;Zhang J;Heffernan TP;Gera S;Kovacs JJ;Marszalek JR;Bristow C;Yan Y;Garcia-Manero G;Kantarjian H;Vassiliou G;Futreal PA;Donehower LA;Takahashi K;Goodell MA
通讯作者：
Goodell MA