| Data source |
GEO: GSE137784
|
| Description |
Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer†and “Liver Tumor†categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis. |
| Key word |
zebrafish; hepatocellular carcinoma; crelox; single-cell rnaseq; beta-catenin;l-fabp gene; recombinase activity; somatic mutations; cell-type; in-vivo; liver; expression; promoter; mouse; classification |
| Publication |
Kalasekar SM, Kotiyal S, Conley C, Phan C et al. Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish. Biol Open 2019 Oct 17;8(10). PMID: 31575545 |
| Abstract |
Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding beta-catenin. HCC-associated CTNNB1 mutations stabilize the beta-catenin protein, leading to nuclear and/or cytoplasmic localization of beta-catenin and downstream activation of Wnt target genes. In patient HCC samples, beta-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in beta-catenin activation are not well understood. To define mechanisms of beta-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated beta-catenin in (1) a small number of hepatocytes in early development; or (2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated beta-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/beta-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish beta-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish beta-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous beta-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis. |
