Oncogenic potential of N-terminal deletion and S45Y mutant β-catenin in promoting hepatocellular carcinoma development in mice

Qiao, Yu; Xu, Meng; Tao, Junyan; Che, Li; Cigliano, Antonio; Monga, Satdarshan P.; Calvisi, Diego F.; Chen, Xin

doi:10.1186/s12885-018-4870-z

Cited by 20 publications

(24 citation statements)

References 23 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings are in keeping with the focal nuclear/cytoplasmic β-catenin localization that we observed in both of our β-catenin-driven HCC models (Fig. 5B–F) (Evason et al, 2015) and that is characteristic of human HCC (Evason et al, 2015; Friemel et al, 2015; Qiao et al, 2018; Rebouissou et al, 2016). Our results support the hypothesis that heterogeneity in β-catenin immunostaining is due to heterogeneous β-catenin activity and not due to limitations in detection of β-catenin protein.…”

Section: Discussionsupporting

confidence: 92%

“…Eighty-seven percent of HCC show intratumor heterogeneity with respect to morphology, immunohistochemistry and/or mutational status of CTNNB1 or TP53 (Friemel et al, 2015). In β-catenin-driven HCC, CTNNB1 mutations are generally ubiquitous within each tumor (Torrecilla et al, 2017), but nuclear and cytoplasmic localization of β-catenin is heterogeneous in both animal models (Evason et al, 2015; Qiao et al, 2018) and patients (Friemel et al, 2015; Rebouissou et al, 2016). For example, we previously reported that hepatocyte-specific expression of activated β-catenin in zebrafish [ Tg(fabp10a : pt-β-cat) ] leads to HCC in 78% of animals by 6 months post fertilization (mpf) (Evason et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

et al. 2019

View full text Add to dashboard Cite

Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. 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. 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.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

et al. 2019

View full text Add to dashboard Cite

show abstract

“…That ⌬(90) generates HBs or HCCs based on whether it is co-expressed with YAP S127A or c-Met lends further credence to the argument that ␤-catenindriven tumorigenesis can be promiscuous and influenced by other co-expressed oncoproteins as well as age-and tissue-specific factors (70). We did not examine the S45Y mutant used by Qiao et al (70) but think it likely that it would also drive HB tumorigenesis in association with YAP S127A , given the robust tumorigenicity of S45A, S45F, and S45P (Fig. 1B).…”

Section: ␤-Catenin Mutations and Hepatoblastoma Phenotypesmentioning

confidence: 99%

β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice

Zhang

Meyfeldt

Wang

et al. 2019

Journal of Biological Chemistry

185

View full text Add to dashboard Cite

Hepatoblastoma (HB) is the most common pediatric liver cancer. Although long-term survival of HB is generally favorable, it depends on clinical stage, tumor histology, and a variety of biochemical and molecular features. HB appears almost exclusively before the age of 3 years, is represented by seven histological subtypes, and is usually associated with highly heterogeneous somatic mutations in the catenin β1 (CTNNB1) gene, which encodes β-catenin, a Wnt ligand–responsive transcriptional co-factor. Numerous recurring β-catenin mutations, not previously documented in HB, have also been identified in various other pediatric and adult cancer types. Little is known about the underlying factors that determine the above HB features and behaviors or whether non-HB–associated β-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB– and non-HB–associated β-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection. We show that all β-catenin mutations, as well as WT β-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-to-cytoplasmic partitioning, and metabolic and transcriptional landscapes were strongly influenced by the identities of the β-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of HB.

show abstract

“…Hydrodynamic tail vein injection was performed basically as previously described. [17][18][19] Briefly, 20 mg of either pT3-EF1ab-catenin-WT, K335I, or N387K construct was mixed with 20 mg pT3-EF1a-c-Met and 1.6 mg pCMV/SB in 2 mL saline. This solution was injected in the lateral tail vein of 6-to 8-week-old WT FVB/N mice purchased from The Jackson Laboratory (Sacramento, CA).…”

Section: Mice and Hydrodynamic Tail Injectionmentioning

confidence: 99%

Oncogenic Mutations in Armadillo Repeats 5 and 6 of β-Catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes

et al. 2020

Self Cite

View full text Add to dashboard Cite

Supplementary Figure 4. AXIN2 RNA expression in b-catenin S37F and K335I knock-in clones. The top panels show the AXIN2 expression levels determined by qRT-PCR (mean ± standard deviation, n ¼ 5) for all analyzed clones. The bottom panels show the results for K335I knock-in clones only. All expression levels are depicted relative to the housekeeping gene GAPDH. Data are presented as mean ± standard deviation. **P < .01; ***P < .001; ****P < .0001. CTR, control. March 2020 Armadillo Repeat 5/6 Mutations of b-Catenin 1043.e6 IgG, immunoglobulin G.

show abstract

Oncogenic potential of N-terminal deletion and S45Y mutant β-catenin in promoting hepatocellular carcinoma development in mice

Cited by 20 publications

References 23 publications

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice

Oncogenic Mutations in Armadillo Repeats 5 and 6 of β-Catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes

Contact Info

Product

Resources

About