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

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.

Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma

“…Besides the classical growth factor signaling pathways discussed above, certain other growth factors and cell proliferation signals contribute to the pathogenesis of several cancers including HCC. This pathway includes genes coding for colony-stimulating factor-1 (CSF1) and its receptor CSF-1R, fibroblast growth factor (FGF)-FGFR and insulin-like growth factor (IGF)-IGFR systems [ 30 – 33 ], and a select set of less well-studied molecules implicated in carcinogenesis such as aurora kinase ( AURKA ) and diphthamide biosynthesis 1 (DPH1) [ 34 , 35 ]. A majority of these eleven genes of this group show a positive correlation with SOCS1 and SOCS3 in the TCGA HCC dataset (Fig.…”

Identification of potential hub genes associated with the pathogenesis and prognosis of hepatocellular carcinoma via integrated bioinformatics analysis

“…Aurora kinase A (encoded by AURKA ) is involved in centrosome duplication, spindle formation, chromosomal amplification and segregation, and cytokinesis, and it plays a significant role in centrosome maturation and mitotic commitment in the late G 2 phase. 70 , 71 Abnormal activity of AURKA promotes tumorigenic progression and transformation via defective control at the checkpoint of mitotic spindle. 72 Meanwhile, AURKA is highly expressed in a variety of human cancers, including breast cancer, 73 lung cancer, 74 gastrointestinal cancer, 75 bladder cancer, 76 and oral cancer.…”

Transcriptomically Revealed Oligo-Fucoidan Enhances the Immune System and Protects Hepatocytes via the ASGPR/STAT3/HNF4A Axis

“…The use of zebrafish as a human disease model has become increasingly common [ 14 ]. Zebrafish hepatocellular carcinoma (HCC) models deepen our understanding of cancer formation via genetic, environmental, and metabolic insults [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Here, we investigate the beneficial effect of OF in hepatocytes and report a new possibility of OF for strengthening the immune system and hepatocellular functions in wild-type zebrafishes.…”