Focal Adhesion Kinase (FAK) Over-Expression and Prognostic Implication in Pediatric Hepatocellular Carcinoma

Abstract

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.

Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects

“…During the last decade, the role of FAK in tumours and the utility of its inhibitors as potential therapeutic agents have been extensively investigated [ 29 ]. FAK was identified as an independent risk factor for HCC, with its overexpression predicting poor prognosis in HCC patients [ 10 , 30 ]. However, to date there is a little evidence of the role of FAK activation, and studies on the effect of clinically translatable FAKi are still in embryo for this tumour.…”

Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetics effects

“…During the last decade, the role of FAK in tumours and the utility of its inhibitors as potential therapeutic agents have been extensively investigated [29]. Even though FAK was identi ed as an independent risk factor for HCC, with its overexpression predicting poor prognosis in HCC patients, currently there is little evidence of the role of FAK activation, and studies on the effect of clinically translatable FAK inhibitors are still in embryo in this tumour [30,31]. We previously demonstrated that FAK silencing may reduce in vitro and in vivo HCC growth by affecting cancer-promoting genes, including the pro-oncogenic EZH2 [13].…”

“…We previously demonstrated that FAK silencing may reduce in vitro and in vivo HCC growth by affecting cancer-promoting genes, including the pro-oncogenic EZH2 [13]. Moreover, it has been reported that FAK may play a key role in the control of liver cancer stem cells proliferation, thus its inhibition and functional interaction with β-catenin has recently been identi ed as a potential strategy to overcome SOR-related resistance associated to this cell subpopulation [31,32]. All these ndings suggest that the network between FAK, epigenetic modi cations and β-catenin might be a useful therapeutic target to treat HCC in presence of SOR resistance.…”

Perspective: The Mechanobiology of Hepatocellular Carcinoma

“…Importantly, these pathways are upregulated in fibrosis [ 50 , 51 , 52 , 53 ]. In particular, FAK is more significantly upregulated in cirrhotic tumors than in those with less dense ECM, suggesting that stiffness-dependent FAK activation plays a role in tumor aggressiveness [ 54 ]. FAK also plays a key role in activating hepatic stellate cells in early fibrosis, increasing expression of α-smooth muscle actin and collagen [ 55 ], both markers of myofibroblasts that are associated with cancer development.…”