1. Academic Validation
  2. 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

  • J Exp Clin Cancer Res. 2021 Aug 20;40(1):262. doi: 10.1186/s13046-021-02061-y.
Juanjuan Luo  # 1 2 Chunjiao Lu  # 2 Meilan Feng 1 Lu Dai 1 Maya Wang 1 Yang Qiu 1 Huilu Zheng 1 Yao Liu 2 Li Li 3 Bo Tang 4 Chuan Xu 5 Yajun Wang 6 Xiaojun Yang 7
Affiliations

Affiliations

  • 1 Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China.
  • 2 Shantou University Medical College, Shantou, China.
  • 3 Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Key Laboratory of Aquatic Science of Chongqing, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China.
  • 4 Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, China.
  • 5 Integrative Cancer Center & Cancer Clinical Research Center, Cancer Center, Sichuan Cancer Hospital & Institute Sichuan, School of Medicine University of Electronic Science and Technology of China, Chengdu, 610041, China.
  • 6 Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China. [email protected].
  • 7 Shantou University Medical College, Shantou, China. [email protected].
  • # Contributed equally.
Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput Anticancer drug screening.

Keywords

Akt; Hepatocellular carcinoma; Pten; Tp53; Zebrafish.

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