Pathology Unit, Bambino Gesù Children's Hospital and IRCCS, 00165 Rome, Italy.
Core Facilities, Bambino Gesù Children's Hospital and IRCCS, 00165 Rome, Italy.
Int J Mol Sci. 2020 Aug 12;21(16):5795. doi: 10.3390/ijms21165795.
Focal adhesion kinase (FAK) is over-expressed and is correlated with aggressiveness in adult hepatocellular carcinoma (HCC). Inhibition of FAK decreases HCC invasiveness by down-regulating Enhancer of Zeste homolog 2 (EZH2), an epigenetic controller, that acts in transcriptional repression of a large number of genes via histone 3 methylation of lysine 27 (H3K27me3). Here, we investigated the hepatic expression of total FAK, EZH2, H3K27me3, and proliferating cell nuclear antigen (PCNA) in 17 pediatric HCCs and 8 healthy livers (CTRL). Quantitative imaging analysis showed that FAK gene/protein expression is up-regulated in HCCs compared to CTRL and, among tumor samples the levels of this gene/protein are significantly higher in cirrhotic HCCs than in a healthy milieu. Accordingly, the protein levels of EZH2 were also significantly increased in HCCs from a cirrhotic background. Intriguingly, the protein expression of FAK, EZH2, and PCNA significantly inversely correlated with tumor size. Finally, in HCC samples, mainly in cirrhotic background, the up-regulation of FAK gene positively correlated with that observed in β-Catenin gene. Conclusion: FAK gene/protein is over-expressed in pediatric HCCs concomitantly to EZH2 protein and β-Catenin gene, with a more significant up-regulation in a cirrhotic background. This triad of interactors deserves further investigations for translational application.
黏着斑激酶（FAK）在成人肝细胞癌（HCC）中过度表达，并与侵袭性相关。FAK 的抑制通过下调增强子结合锌指蛋白 2（EZH2）来降低 HCC 的侵袭性，EZH2 是一种表观遗传控制器，通过组蛋白 3 赖氨酸 27 甲基化（H3K27me3）在转录水平抑制大量基因的表达。在这里，我们研究了 17 例小儿 HCC 和 8 例健康肝脏（CTRL）中总 FAK、EZH2、H3K27me3 和增殖细胞核抗原（PCNA）的肝表达。定量成像分析显示，与 CTRL 相比，FAK 基因/蛋白在 HCC 中上调，并且在肿瘤样本中，这种基因/蛋白在肝硬化 HCC 中的水平明显高于健康环境。相应地，EZH2 的蛋白水平在肝硬化背景下的 HCC 中也显著增加。有趣的是，FAK、EZH2 和 PCNA 的蛋白表达与肿瘤大小呈显著负相关。最后，在 HCC 样本中，主要在肝硬化背景下，FAK 基因的上调与β-连环蛋白基因的上调呈正相关。结论：FAK 基因/蛋白在小儿 HCC 中过度表达，与 EZH2 蛋白和β-连环蛋白基因同时表达，在肝硬化背景下表达更为显著。这一组相互作用的因子值得进一步研究，以进行转化应用。
