Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish.
Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish.
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pten 和 tp53 肝脏特异性突变之间的协同遗传诱导斑马鱼肝癌发生
DOI：
10.1186/s13046-021-02061-y
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发表时间：
2021-08-20
期刊：
影响因子：
--
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Luo J;Lu C;Feng M;Dai L;Wang M;Qiu Y;Zheng H;Liu Y;Li L;Tang B;Xu C;Wang Y;Yang X
肝癌，主要是肝细胞癌，是世界范围内最致命的癌症之一，由于对肝癌发生机制的了解不足，预后较差。以往的研究表明，PTEN和TP53突变是肝癌发生中最常见的两种遗传事件。在这里，我们阐明了斑马鱼肝癌发生过程中异常Pten和Tp53通路之间的串扰。我们利用CRISPR/Cas9系统建立了几种具有pten和tp53单或双组织特异性突变的转基因斑马鱼系，以遗传诱导肝脏肿瘤发生。接下来，我们通过形态学和组织学检测来研究Pten和Tp53信号通路在斑马鱼肝癌发生中的作用。我们证明了Pten缺失单独诱导肝癌发生的效率很低，而tp53的单一突变不能诱导斑马鱼肝脏组织中的肿瘤形成。此外，pten和tp53双突变的斑马鱼比单突变的斑马鱼表现出更高的肿瘤发生率、更高的组织学等级和更短的生存时间，这表明这两种信号通路在斑马鱼肝癌发生的开始和进展的动态生物学事件中起着重要作用。进一步的组织学和病理学分析显示斑马鱼和人类肝脏组织产生的肿瘤有显著的相似性。此外，Akt特异性抑制剂MK-2206有效抑制斑马鱼肝癌的发生。我们的发现将为遗传学研究肝癌发生提供临床前动物模型，并为高通量抗癌药物筛选提供有用的平台。在线版本包含补充资料，网址为10.1186/s13046-021-02061-y。
Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening. The online version contains supplementary material available at 10.1186/s13046-021-02061-y.
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影响因子：
50.3
作者：
Blackburn JS;Liu S;Wilder JL;Dobrinski KP;Lobbardi R;Moore FE;Martinez SA;Chen EY;Lee C;Langenau DM
通讯作者：
Langenau DM
影响因子：
5.4
作者：
Aubrey, Brandon J.;Strasser, Andreas;Kelly, Gemma L.
通讯作者：
Kelly, Gemma L.
影响因子：
45.3
作者：
Goessling, Wolfram;North, Trista E.;Zon, Leonard I.
通讯作者：
Zon, Leonard I.
DOI：
10.1073/pnas.0406252102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Berghmans, S;Murphey, RD;Look, AT
通讯作者：
Look, AT
影响因子：
11.8
作者：
Ablain J;Durand EM;Yang S;Zhou Y;Zon LI
通讯作者：
Zon LI