Functions and therapeutic value of focal adhesion kinase signaling during hepatocellular carcinoma development and progression
Authors: Anna Alisi, Clara Balsano
Journal: Hepatology (2009)

We appreciate the article by Wu et al. in a recent issue of HEPATOLOGY.1 In this study, the authors demonstrated that the overexpression of epidermal growth factor–like domain 7 (Egfl7) was closely associated with poor prognosis in hepatocellular carcinomas (HCCs). In addition, they investigated the role of Egfl7 in the development and progression of HCC by silencing its expression via transfecting a specific small interfering RNA in HCC cell lines. Silencing of Egfl7 expression caused no changes in cell growth, even if it resulted in a relevant inhibition of cell migration, which appeared mediated by the phosphorylation of focal adhesion kinase (FAK). All these effects were reverted by the use of an epidermal growth factor receptor (EGFR) inhibitor. Interestingly, the existence of a critical role of Egfl7/FAK pathway in controlling HCC was also demonstrated in a mouse model of intrahepatic and pulmonary metastases. FAK phosphorylation is a critical event in processes of cell migration, adhesion, and growth of several cancer cells.2 The role of FAK in the invasion, metastasis, and prognosis of HCC was not completely unknown. In fact, a previous work reported that the increased messenger RNA expression of FAK was well correlated with tumor size and serum levels of alpha-fetoprotein, indicating an important prognostic value to evaluate the survival of patients with HCC.3 In addition, more recently, FAK and Src have been demonstrated to be overexpressed and activated in HCC tissues.4 However, the mechanism by which FAK may contribute to HCC pathogenesis and progression has still not been elucidated.5 FAK is a tyrosine kinase that upon integrin ligation cross-interacts with Src, enhancing the phosphorylation of downstream targets involved in migration pathways, such as paxillin.6 This mechanism also seems to be conserved in human hepatoma cell lines, but it is still unknown which upstream signaling molecules might be involved in the Src/FAK/paxillin interaction.7 The mechanism proposed by Wu and colleagues is very intriguing. The authors suggest that the regulation of FAK phosphorylation and activity might be influenced by the binding of epidermal growth factor (EGF) to its membrane receptor (EGFR). This hypothesis is not only suggestive of a possible role of EGFR-FAK axis in HCC progression, but also in tumor development. In fact, the EGF-EGFR combination is engaged in extensive cross-talk with other signaling pathways which control cell proliferation and inflammatory response.8 These findings, once again, encourage the use of EGFR inhibitors as potential therapeutic agents during HCC and suggest that FAK might be a possible novel potential target in therapy.9, 10 Finally, we believe that these last considerations should prompt in vivo and in vitro studies to explore anticancer properties of small molecules (e.g., PF-573,228; PF-562,271; and NVP-226) able to antagonize FAK activity in HCC. Anna Alisi Ph.D.*, Clara Balsano M.D. , * Liver Unit, Bambino Gesù Children's Hospital and, Research Institute, Rome, Italy, Department of Internal Medicine, University of L'Aquila, L'Aquila, Italy.