Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation

Huang, Shin-Jie; Cheng, Chih-Lun; Chen, Jim-Ray; Gong, Hong‐Yi; Liu, Wangta; Wu, Jen‐Leih

doi:10.1016/j.bbrc.2017.06.164

Cited by 12 publications

(30 citation statements)

References 37 publications

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“…In the course of these studies, we found that cyclin D3–cdk4 phosphorylates C/EBPα at Ser193 and increases formation of C/EBPα‐p300 complexes, which in turn activate enzymes of TG synthesis and cause hepatic steatosis . In addition to cdk4, several recent papers provide evidence that a number of strong initiators of liver proliferation and oncogenes are elevated in human liver biopsies from patients with NAFLD and in animal models of NAFLD at early stages of the disease . Previous studies suggested that hepatic steatosis causes further steps of NAFLD.…”

Section: Discussionmentioning

confidence: 92%

“…In agreement, it has recently been shown that some strong initiators of liver proliferation and oncogenes are elevated in human liver biopsies from patients and in animal models with NAFLD. These proliferative markers include the elevation of gankyrin (Gank), cyclin‐dependent kinase 4 (cdk4), and cyclin D3 and activation of the E2F1 pathway . Several recent reports showed that inhibition of cdk4 prevented and reversed the NAFLD phenotype .…”

mentioning

confidence: 99%

“…Several recent reports demonstrated that Gank might be a critical driver of NAFLD. It has been shown that the Gank transgenic zebrafish model spontaneously develops hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC) . Gank is elevated in mice with HFD‐mediated NASH and in patients with NASH .…”

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confidence: 99%

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Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) involves development of hepatic steatosis, fibrosis, and steatohepatitis. Because hepatic steatosis appears first in NAFLD animal models, the current therapy development focuses on inhibition of hepatic steatosis, suggesting that further steps of NAFLD will be also inhibited. In this report, we show that the first event of NAFLD is liver proliferation, which drives fibrosis in NAFLD. We have deleted a strong driver of liver proliferation, gankyrin (Gank), and examined development of NAFLD in this animal model under conditions of a high‐fat diet (HFD). We found that proliferating livers of wild‐type mice develop fibrosis; however, livers of Gank liver‐specific knockout (GLKO) mice with reduced proliferation show no fibrosis. Interestingly, an HFD causes the development of strong macrovesicular steatosis in GLKO mice and is surprisingly associated with improvements in animal health. We observed that key regulators of liver biology CCAAT/enhancer binding protein α (C/EBPα), hepatocyte nuclear factor 4α (HNF4α), p53, and CUG repeat binding protein 1 (CUGBP1) are elevated due to the deletion of Gank and that these proteins support liver functions leading to healthy conditions in GLKO mice under an HFD. To examine the role of one of these proteins in the protection of liver from fibrosis, we used CUGBP1‐S302A knockin mice, which have a reduction of CUGBP1 due to increased degradation of this mutant by Gank. These studies show that reduction of CUGBP1 inhibits steatosis and facilitates liver proliferation, leading to fibrosis and the development of liver tumors. Conclusion: Liver proliferation drives fibrosis, while steatosis might play a protective role. Therapy for NAFLD should include inhibition of proliferation rather than inhibition of steatosis.

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

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Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

et al. 2019

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“…Liver-specific overexpression of Gank has been shown to facilitate the development of liver cancer under DEN/CCl 4 -mediated cancer 16 . Overexpression of Gank in livers of zebra fish has recently been shown to develop spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma 17 .…”

Section: Introductionmentioning

confidence: 99%

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma

et al. 2018

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Hepatoblastoma (HBL) is a pediatric liver cancer that affects children under the age of three. Reduction of tumor suppressor proteins (TSPs) is commonly seen in liver cancer. However, in our studies we find that aggressive, chemo-resistant HBLs exhibit an elevation of TSPs. HBL patients with a classic phenotype have reduced TSP levels, but patients with aggressive HBL express elevated TSPs that undergo posttranslational modifications, eliminating their tumor suppression activities. Here we identify unique aggressive liver cancer domains (ALCDs) that are activated in aggressive HBL by PARP1-mediated chromatin remodeling leading to elevation of modified TSPs and activation of additional cancer pathways: WNT signaling and β-catenin. Inhibition of PARP1 blocks activation of ALCDs and normalizes expression of corresponding genes, therefore reducing cell proliferation. Our studies reveal PARP1 activation as a mechanism for the development of aggressive HBL, further suggesting FDA-approved PARP1 inhibitors might be used for treatment of patients with aggressive HBL.

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“…Zebrafish larvae are a valuable model to study the early cellular and molecular events involved in liver cancer progression (de Oliveira et al, 2019; Huang et al, 2017; Nguyen et al, 2012; Yan et al, 2015; Yan et al, 2017; Zhao et al, 2016). Next, we wanted to determine if FLC transgenic larvae displayed early malignancy features.…”

Section: Resultsmentioning

confidence: 99%

DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma

Oliveira¹,

Houseright²,

Korte³

et al. 2019

Preprint

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Fibrolamellar Hepatocellular Carcinoma (FLC) is a rare liver cancer that primarily affects adolescents and young adults. Up to now there is only one identified molecular target responsible for driving the disease, the chimeric protein encoded by DNAJB1-PRKACA (J-PKAca). Immune cells have been identified as key players in liver cancer biology, however the effect of J-PKAca on inflammation in the liver microenvironment is not known. Here we report a new zebrafish model of FLC with non-invasive live imaging capabilities that allows the study of the interactions between immune cells and transformed hepatocytes. We found that overexpression of the dnajb1a-prkcaaa fusion gene specifically in hepatocytes induces early malignancy features in FLC transgenic larvae, such as increased liver and hepatocyte size. In addition, this aberrant form of PKA promotes a pro-inflammatory liver microenvironment by increasing the number of neutrophils and macrophages in the liver area and inducing macrophage polarization to a pro-inflammatory phenotype. Increased caspase-a activity was also found in the liver of FLC transgenic larvae. Importantly, pharmacological inhibition of TNFα secretion and caspase-a activity decreased liver size and inflammation. Overall, these findings suggest that inflammation may be an early feature of FLC involved in progression, and that targeting TNFαand caspase-1 may be beneficial in treating FLC.

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Inducible liver-specific overexpression of gankyrin in zebrafish results in spontaneous intrahepatic cholangiocarcinoma and hepatocellular carcinoma formation

Cited by 12 publications

References 37 publications

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

Liver Proliferation Is an Essential Driver of Fibrosis in Mouse Models of Nonalcoholic Fatty Liver Disease

PARP1 activation increases expression of modified tumor suppressors and pathways underlying development of aggressive hepatoblastoma

DNAJB1-PRKACA fusion induces liver inflammation in zebrafish model of Fibrolamellar Hepatocellular Carcinoma

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