Gradually elevated expression of Gankyrin during human hepatocarcinogenesis and its clinicopathological significance

Gankyrin is an important oncoprotein that is overexpressed in human hepatocellular carcinoma (HCC). However, the gradual alteration of Gankyrin in successive stages during human HCC development and the mechanism of Gankyrin-mediated hepatocarcinogenesis remain largely unknown. In this study, we evaluated the pattern and level of Gankyrin protein expression using immunohistochemistry in various liver tissues, including normal liver, chronic hepatitis, cirrhosis, adenomatous hyperplasia (AH), and HCC tissues, to analyze its clinicopathological significance. Furthermore, we stably transfected the shRNA-Gan vector, which targets human Gankyrin, into HepG2 cells to assess the role of Gankyrin in cell proliferation and tumorigenicity. The expression level of Gankyrin in the cytoplasm, nucleus, and whole cell was gradually elevated during consecutive stages of hepatocarcinogenesis. The nuclear Gankyrin level in AH was significantly higher than that in normal liver, chronic hepatitis, and cirrhotic tissues. The cytoplasmic, nuclear, and total cellular Gankyrin expression levels in HCC were significantly correlated with capsular invasion and intrahepatic metastasis. Silencing Gankyrin expression using shRNA-Gan repressed tumor cell proliferation, tumorigenicity, migration, and invasion in vitro. Our findings demonstrate that Gankyrin is aberrantly expressed beginning at the initiation stage and plays an important role in the initiation, promotion, and progression of hepatocarcinogenesis.