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A Novel AURKA Mutant-Induced Early-Onset Severe Hepatocarcinogenesis Greater than Wild-Type via Activating Different Pathways in Zebrafish

1
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan
2
Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan
3
Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
4
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
5
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan
6
Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
7
Ph.D. Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
*
Authors to whom correspondence should be addressed.
Cancers 2019, 11(7), 927; https://doi.org/10.3390/cancers11070927
Received: 24 May 2019 / Revised: 24 June 2019 / Accepted: 26 June 2019 / Published: 2 July 2019
(This article belongs to the Special Issue Liver Cancer and Potential Therapeutic Targets)
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Abstract

Aurora A kinase (AURKA) is an important regulator in mitotic progression and is overexpressed frequently in human cancers, including hepatocellular carcinoma (HCC). Many AURKA mutations were identified in cancer patients. Overexpressing wild-type Aurka developed a low incidence of hepatic tumors after long latency in mice. However, none of the AURKA mutant animal models have ever been described. The mechanism of mutant AURKA-mediated hepatocarcinogenesis is still unclear. A novel AURKA mutation with a.a.352 Valine to Isoleucine (V352I) was identified from clinical specimens. By using liver-specific transgenic fish overexpressing both the mutant and wild-type AURKA, the AURKA(V352I)-induced hepatocarcinogenesis was earlier and much more severe than wild-type AURKA. Although an increase of the expression of lipogenic enzyme and lipogenic factor was observed in both AURKA(V352I) and AURKA(WT) transgenic fish, AURKA(V352I) has a greater probability to promote fibrosis at 3 months compared to AURKA(WT). Furthermore, the expression levels of cell cycle/proliferation markers were higher in the AURKA(V352I) mutant than AURKA(WT) in transgenic fish, implying that the AURKA(V352I) mutant may accelerate HCC progression. Moreover, we found that the AURKA(V352I) mutant activates AKT signaling and increases nuclear β-catenin, but AURKA(WT) only activates membrane form β-catenin, which may account for the differences. In this study, we provide a new insight, that the AURKA(V352I) mutation contributes to early onset hepatocarcinogenesis, possibly through activation of different pathways than AURKA(WT). This transgenic fish may serve as a drug-screening platform for potential precision medicine therapeutics. View Full-Text
Keywords: hepatocellular carcinoma (HCC); zebrafish; Aurora A kinase (AURKA); β-catenin; AKT signaling pathway hepatocellular carcinoma (HCC); zebrafish; Aurora A kinase (AURKA); β-catenin; AKT signaling pathway
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Su, Z.-L.; Su, C.-W.; Huang, Y.-L.; Yang, W.-Y.; Sampurna, B.P.; Ouchi, T.; Lee, K.-L.; Wu, C.-S.; Wang, H.-D.; Yuh, C.-H. A Novel AURKA Mutant-Induced Early-Onset Severe Hepatocarcinogenesis Greater than Wild-Type via Activating Different Pathways in Zebrafish. Cancers 2019, 11, 927.

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