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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and ranks as the third leading cause of mortality worldwide [1,2], and there is still no effective therapy available due to its heterogeneity [3]
We demonstrated that the wild-type Aurora A kinase (AURKA) and the V352I mutant can differentially activate those signaling axes in transgenic fish during hepatocarcinogenesis, which provides a new insight to AURKA-mediated liver tumorigenesis
The level of AURKA is well correlated with a high grade and stage of HCC, indicating that overexpression of AURKA plays a role in the development and progression of HCC
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and ranks as the third leading cause of mortality worldwide [1,2], and there is still no effective therapy available due to its heterogeneity [3]. In the era of precision medicine, to understand the real causative factors underlying the carcinogenesis, and provide treatment with precise personalized medicine, is extremely important and remains the most effective therapy for the HCC [4]. Genome-wide association study (GWAS) technology enables the discovery of many genetic risk factors and mutations related to HCC [6]. Animal models for functional analysis are warranted to confirm the roles of those mutations in hepatocarcinogenesis and develop precision medicine against those novel mutants
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