靶向 WIP1 和 PARP 可诱导肝癌合成致死。

Co-targeting WIP1 and PARP induces synthetic lethality in hepatocellular carcinoma.

机构信息

Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Institute of Zhejiang University, Sir Run Run Shaw Hospital, Cancer Center, School of Medicine, Zhejiang University, Hangzhou, 310016, Zhejiang, China.

Department of Medical Oncology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.

出版信息

Cell Commun Signal. 2022 Mar 28;20(1):39. doi: 10.1186/s12964-022-00850-2.

DOI:10.1186/s12964-022-00850-2

PMID:35346236

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8962187/

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

摘要

背景

肝细胞癌（HCC）是最致命的癌症之一。由于缺乏有效的治疗策略，晚期 HCC 患者的预后非常差。本研究旨在为 HCC 提供新的见解，以开发 HCC 管理的新策略。

方法

在 HCC 细胞、异种移植模型、用 WIP1 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 WIP1（野生型 p53 诱导蛋白磷酸酶 1）在 HCC 中的作用。通过基因集富集分析、western blot、彗星试验和免疫荧光评估 DNA 损伤。

结果

WIP1 的高表达与 HCC 患者的不良预后相关。WIP1 的遗传和化学抑制可显著降低 HCC 细胞的增殖。此外，WIP1 敲除可延缓 DEN 诱导的小鼠肝致癌作用。在机制上，WIP1 抑制通过增加 H2AX 磷酸化（γH2AX）诱导 DNA 损伤。因此，抑制 WIP1 和 PARP 通过增加 DNA 损伤在 HCC 中体外和体内诱导合成致死性。