Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

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.

Mechanically sensitive HSF1 is a key regulator of left-right symmetry breaking in zebrafish embryos

“…Further, we treated embryos with an Akt inhibitor (MK-2206), which has been reported to block Akt signaling pathway in zebrafish. 51 The results showed a significant downregulation of left-biased activation of HSF1 by Akt inhibition ( Figures 6 C and 6D). These results suggest that Ca 2+ -Akt signaling axis is essential for the activation of HSF1 in KV.…”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…Individuals and lines have been created that exhibit analogs of human somatic diseases such as cataract [ 49 , 50 ], myopia [ 51 ], exfoliative syndrome [ 52 ], retinal dysfunction [ 53 , 54 ], congenital heart defect [ 55 ], cardiac hypertrophy [ 56 ], dilated cardiomyopathy [ 57 ], arrhythmia [ 58 ], autoinflammatory syndrome [ 59 ], metabolic syndrome [ 60 ], diabetes and obesity [ 61 ], tuberculosis [ 62 ], thrombocytopenia [ 63 ], pediatric intestinal pseudoobstruction [ 64 ], pediatric cirrhosis [ 65 ], congenital hypothyroidism [ 66 ], fatty or alcoholic hepatosis [ 67 ], and scoliosis [ 68 , 69 ]. Genome editing has been used to model human tumors such as liver cancer [ 70 ], paraganglioma [ 71 ], skin melanoma [ 72 ], and epithelioid sarcoma [ 73 ]. Among neurologic diseases, amyotrophic lateral sclerosis [ 74 ], epilepsy [ 75 , 76 , 77 , 78 , 79 ], Hirschprung’s disease [ 80 ], autism [ 81 , 82 , 83 , 84 ], spastic paraplegia [ 85 ], restless legs syndrome [ 86 ], insomnia [ 87 ], microcephaly [ 46 ], neurotransmitter function of dopamine [ 88 ], monoamine [ 89 ], and others [ 90 , 91 ].…”