Abstract
BackgroundLiver 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.MethodsWe 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.ResultsWe 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.ConclusionOur findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.
Highlights
Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis
The effective ptena, ptenb, and tp53 guide RNA (gRNA) were identified by T7E1 mutagenesis assay [48] and DNA sequencing after co-injection with Cas9 mRNA into one-cell-stage zebrafish embryos (Supplemental Fig. 1a-c)
Our results revealed that the spontaneous Hepatocellular carcinoma (HCC) developed when pten are deleted in zebrafish, which might have implications for cancer therapy, whereas the deficiency of Tp53 is not required for the initiation of HCC, indicating that Akt/Pten pathway might be critical for the initiation pathway of hepatocarcinogenesis in zebrafish
Summary
Mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Hepatocellular carcinoma (HCC) accounts for over 90% of primary liver cancers [2] It generally has a poor prognosis, as it is often diagnosed at a late stage; even with treatment, HCC has a high recurrence rate after resection, and a lack of curative therapies for advanced-stage disease [3]. Previous reports indicated that multiple risk factors, including infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), chronic alcohol consumption, aflatoxin contamination, and metabolic disease, are highly correlative with HCC tumorigenesis [6,7,8] These factors play critical roles in regulating multiple oncogenes or tumour suppressor genes to activate tumorigenesis-related signalling pathways [9, 10]. Several previous studies investigated the potential roles of PTEN and TP53 in HCC [21, 22], the crosstalk between PTEN and TP53 signalling pathways and the dynamic histological features involved in the initiation and development of HCC require further exploration
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