The role of FLT3 in hepatocellular carcinogenesis

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types and it has a high mortality rate. Its high incidence is a consequence of lack of biomarkers that could track the progression of the disease. Identification of a marker, which involves in different stages of cancer progression, through fibrosis to HCC, would be a good candidate for diagnosis, prediction of prognosis and targeted therapies. Therefore we decided to identify a novel marker for HCCs, to overcome these consequences. Previously our group has shown that oval cell marker FLT3, a known hematopoetic stem cell marker and which is known to be constitutively active in many of the leukemias, has a role in liver regeneration. Also our immunohistochemical analysis of cirrhotic liver tissues have shown that FLT3 is expressed in liver injury. Therefore, we decided to analyze the role of FLT3 in hepatocellular carcinogenesis. Expression analysis of FLT3 on mRNA and protein level and the expression analysis of adult stem cell, cancer stem cell, and epithelial and mesenchymal lineage markers on mRNA level in 14 HCC cell lines (HepG2, Hep3B, Hep40, Huh7, PLC/PRF/5, Mahlavu, Focus, Sk-Hep-1, Snu182, Snu387, Snu398, Snu423, Snu449, Snu475) was performed. Four of these cell lines (Snu182, Snu398, Huh7 and Hep40) were chosen due to their different expression levels of FLT3 and the functional role of FLT3 in HCCs was assessed by blocking its activity by a small molecule inhibitor K-252a Nocardiopsis sp.. Functional studies had shown that upon inhibitor treatment, subcellular localization of the protein was changed and its invasion ability in vitro was impaired. Also nude mice xenografts had shown that upon inhibitor treatment tumor forming ability of FLT3 expressing cells were highly diminished. Therefore we suggest that FLT3 has a role in hepatocellular carcinogenesis and it might be another link between liver regeneration and hepatocellular carcinogenesis.