Loss of Apc Cooperates with Activated Oncogenes to Induce Liver Tumor Formation in Mice

Zhang, Yi; Liang, Benjia; Song, Xinhua; Wang, Haichuan; Evert, Matthias; Zhou, Yi; Calvisi, Diego F.; Tang, Liling; Chen, Xin

doi:10.1016/j.ajpath.2021.01.010

Cited by 4 publications

(4 citation statements)

References 68 publications

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“…In addition, similar to YAP, simultaneous upregulation of AKT in TAZ-overexpressing mouse livers induced rapid cholangiocarcinogenesis, suggesting the requirement of AKT for TAZ and YAP full oncogenic potential. According to this hypothesis, previous evidence from our laboratory indicates that TAZ can induce hepatocellular carcinoma and hepatoblastoma development in the mouse via hydrodynamic transfection only in association with other molecular events, such as overexpression of c-Myc, c-Met, and mutant β-catenin, or loss of APC [ 33 , 46 , 47 ]. The cellular and molecular mechanisms induced by collaborating oncogenes allowing TAZ to express its malignant properties remain unaddressed.…”

Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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Background Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive primary liver tumor with increasing incidence worldwide, dismal prognosis, and few therapeutic options. Mounting evidence underlines the role of the Hippo pathway in this disease; however, the molecular mechanisms whereby the Hippo cascade contributes to cholangiocarcinogenesis remain poorly defined. Methods We established novel iCCA mouse models via hydrodynamic transfection of an activated form of transcriptional coactivator with PDZ-binding motif (TAZ), a Hippo pathway downstream effector, either alone or combined with the myristoylated AKT (myr-AKT) protooncogene, in the mouse liver. Hematoxylin and eosin staining, immunohistochemistry, electron microscopy, and quantitative real-time RT-PCR were applied to characterize the models. In addition, in vitro cell line studies were conducted to address the growth-promoting roles of TAZ and its paralog YAP. Results Overexpression of TAZ in the mouse liver triggered iCCA development with very low incidence and long latency. In contrast, co-expression of TAZ and myr-AKT dramatically increased tumor frequency and accelerated cancer formation in mice, with 100% iCCA incidence and high tumor burden by 10 weeks post hydrodynamic injection. AKT/TAZ tumors faithfully recapitulated many of the histomolecular features of human iCCA. At the molecular level, the development of the cholangiocellular lesions depended on the binding of TAZ to TEAD transcription factors. In addition, inhibition of the Notch pathway did not hamper carcinogenesis but suppressed the cholangiocellular phenotype of AKT/TAZ tumors. Also, knockdown of YAP, the TAZ paralog, delayed cholangiocarcinogenesis in AKT/TAZ mice without affecting the tumor phenotype. Furthermore, human preinvasive and invasive iCCAs and mixed hepatocellular carcinoma/iCCA displayed widespread TAZ activation and downregulation of the mechanisms protecting TAZ from proteolysis. Conclusions Overall, the present data underscore the crucial role of TAZ in cholangiocarcinogenesis

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Section: Discussionmentioning

confidence: 99%

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Cigliano

Zhang

Ribback

et al. 2022

J Exp Clin Cancer Res

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“…Accordingly, the FAP-HCAs in our collective lack signs for an increased risk of malignant transformation, which in contrast is the case for beta-catenin-activated HCA, and there is only a single case report on a FAP-HCA with malignant transformation in the literature [ 25 ]. Loss-of-function mutations in APC are also rarely found in HCC (less than 3%) [ 38 ]. Accordingly, only ten cases of FAP-associated HCCs have been described in the literature so far.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the age of the patients at the time of HCA diagnosis (reviewed in this article) and the age of the patients at the time of HCC diagnosis did not differ significantly. Mutational inactivation of the APC gene alone was also found to be insufficient to promote hepatocarcinogenesis in a sgApc mouse model, and additional genetic events were needed to induce HCC formation [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Integrated genotype–phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas

Tóth,

Kirchner,

Longerich

et al. 2023

Virchows Arch

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Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by numerous colorectal adenomas. In addition, FAP patients may develop extraintestinal manifestations. Several cases of hepatocellular adenomas (HCA) detected accidentally in FAP patients have raised the so-far unsolved question of whether they represent a specific manifestation of FAP or a mere coincidence. To investigate the incidence of liver tumors in FAP patients, we analyzed our diagnostic database from 1991 to 2021. Among the 58 hepatic mass lesions identified, five HCAs occurring in three patients with FAP were identified, and comprehensive morphological, immunohistological, and molecular analysis employing targeted next-generation sequencing was conducted for characterization. The HCAs in this study showed no cytological or histological atypia. They displayed a diffuse, strong positivity for glutamine synthetase but no nuclear beta-catenin immunostaining. In two patients, the adenomas showed moderate immunoreactivity against serum amyloid A. Consistent with the diagnosis of FAP, molecular profiling revealed a pathogenic germline mutation of the APC gene in all analyzed adenomas as well as deleterious somatic second hits. All somatic mutations were localized between codons 1345 and 1577. No mutations were found in the catenin beta 1 gene. HCA in FAP patients can be a specific, although rare, neoplastic manifestation of this inborn disease and represents a distinct subgroup of HCAs. These benign tumors represent an important differential diagnosis for hepatic metastases in FAP patients and require adequate clinical and molecular (diagnostic) assessments for optimal patient guidance.

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“… 7 , 8 HCC has become a major health problem worldwide owing to its late detection, increasing incidence, and high mortality. 9 , 10 , 11 Therefore, novel, safe, and efficient anti-HCC drugs must be developed and their mechanisms of action must be elucidated. 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

A cell transmembrane peptide chimeric M(27–39)-HTPP targeted therapy for hepatocellular carcinoma

Deng

Yan

et al. 2023

iScience

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Loss of Apc Cooperates with Activated Oncogenes to Induce Liver Tumor Formation in Mice

Cited by 4 publications

References 68 publications

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

The Hippo pathway effector TAZ induces intrahepatic cholangiocarcinoma in mice and is ubiquitously activated in the human disease

Integrated genotype–phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas

A cell transmembrane peptide chimeric M(27–39)-HTPP targeted therapy for hepatocellular carcinoma

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