Su Zhong-Liang, Su Chien-Wei, Huang Yi-Luen, Yang Wan-Yu, Sampurna Bonifasius Putera, Ouchi Toru, Lee Kuan-Lin, Wu Chen-Sheng, Wang Horng-Dar, Yuh Chiou-Hwa
Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan.
Cancers (Basel). 2019 Jul 2;11(7):927. doi: 10.3390/cancers11070927.
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.
极光激酶A（AURKA）是有丝分裂进程中的重要调节因子，在包括肝细胞癌（HCC）在内的人类癌症中经常过度表达。在癌症患者中发现了许多AURKA突变。在小鼠中过表达野生型Aurka，经过长时间潜伏期后肝肿瘤发生率较低。然而，从未有过AURKA突变动物模型的报道。突变型AURKA介导肝癌发生的机制仍不清楚。从临床标本中鉴定出一种新的AURKA突变，即第352位氨基酸由缬氨酸变为异亮氨酸（V352I）。通过使用过表达突变型和野生型AURKA的肝脏特异性转基因鱼，发现AURKA（V352I）诱导的肝癌发生比野生型AURKA更早且更严重。虽然在AURKA（V352I）和AURKA（WT）转基因鱼中均观察到脂肪生成酶和脂肪生成因子的表达增加，但与AURKA（WT）相比，AURKA（V352I）在3个月时促进纤维化的可能性更大。此外，转基因鱼中AURKA（V352I）突变体的细胞周期/增殖标志物表达水平高于AURKA（WT），这意味着AURKA（V352I）突变体可能加速HCC进展。此外，我们发现AURKA（V352I）突变体激活AKT信号并增加核β-连环蛋白，但AURKA（WT）仅激活膜形式的β-连环蛋白，这可能是造成差异的原因。在本研究中，我们提供了一个新的见解，即AURKA（V352I）突变可能通过激活与AURKA（WT）不同的途径促成早期肝癌发生。这种转基因鱼可作为潜在精准医学治疗药物筛选平台。
