Emerging roles of FGF signaling in hepatocellular carcinoma

Liver cancer is the fifth most common malignance in the world. It has been known that 90% of liver cancers are hepatocellular carcinoma (HCC). It is estimated that more than 740,000 new cases of HCC were diagnosed and approximately 700,000 deaths were occurred worldwide. In the USA, 35,660 people will be diagnosed with HCC and 24,550 patients will die from HCC in year 2015. In China, more than 400,000 new cases will be developed and 370,000 patients will die due to this deadly disease. Although surgical resection and liver transplantation have been improved, the 5-year survival rate has no significant decrease in part due to the fact that most patients are in the late stage at diagnosis. Additionally, many HCC patients exhibit low sensitivity to standard radiotherapy and chemotherapy. For example, sorafenib is the standard drug for the treatment of advanced HCC cases; however, the median overall survival of these HCC patients is still less than 1 year partly due to drug resistance. Therefore, it is pivotal to discover the new therapeutic drugs for the treatment of HCC patients. Emerging evidence has suggested that hepatitis C virus (HCV) and hepatitis B virus (HBV) infection are important risk factors for the incidence of HCC. In addition, obesity, diabetes and nonalcoholic steatohepatitis have been found to contribute to HCC incidence. Without a doubt, the presence of cirrhosis is the overriding risk factor for HCC. In recent years, several lines of evidence has defined that some genes and cellular signaling pathways play a key role in the development and progression of HCC, including Notch, PI3K (phosphatidylinositol 3-Kinase)/Akt, extracellularregulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), Hedeghog, and Wnt pathways. Moreover, some growth factor signaling pathways such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) have also been emerged as critical players in tumorigenesis including liver carcinogenesis. Among some of these pathways, FGF has recently gained high attention in HCC development and progression. Therefore, in this article, we will briefly describe recent advances in the physiological function and molecular mechanism of FGF in HCC. We also present the current chemical inhibitors of FGF/FGFR and natural agents that inactivate FGF signaling pathway. Lastly, we will discuss whether FGF/FGFR could be the prognostic markers and/ or potential targets for the treatment of HCC patients.