Enhanced expression of the protein kinase substrate annexin I in human hepatocellular carcinoma

Annexin (AX) constitutes a new family of Ca²⁺-dependent membrane- binding proteins; 13 of them have been described. Among these, annexin-I (AX- I) has displayed many biological functions in vitro. Its actual role in vivo, however, remains unknown. We already reported that AX-I was expressed in proliferating (regenerating) hepatocytes at both protein and messenger RNA (mRNA) levels. The role of AX-I in human hepatocellular carcinoma (HCC) remains obscure. In this study, the amounts of AX-I at protein and mRNA levels, as well as its localization, have been determined in the normal human liver, chronic hepatitis liver, and nontumorous and tumorous portions of HCC. AX-I was rarely found in normal and chronic liver tissues, whereas it is overexpressed at both the transcriptional and translational levels in tumorous and nontumorous regions of HCC. In addition, more AX-I was expressed in the tumorous portion than the nontumorous portion of HCC. AX-I was present in the hepatocytes and HCC cells, localized mainly in the cytoplasm. AX-I was overexpressed in poorly differentiated cancer cells. Furthermore, AX-I was tyrosine-phosphorylated in HCC. We also found that some of the AX-I-positive hepatocytes in the nontumorous tissues were derived from a particular subset of parenchymal cells (stem or oval cells). These results indicate that AX-I plays an important role in the malignant transformation process leading to HCC and that it is closely related to the histological grade of HCC. HCC would offer a novel tool with which to study the function of AX-I in malignant transformation.