Increased Midkine Expression in Hepatocellular Carcinoma

CONTEXT: Midkine (MK) is a novel heparin-binding growth factor whose gene was identified in embryonal carcinoma cells in early stages of retinoic acid-induced differentiation. OBJECTIVE: To examine the overexpression of MK in hepatocellular carcinoma (HCC). METHODS: Seventy-seven primary HCC specimens from patients aged 17 to 72 years (63 men and 14 women) were examined. Histologically, 16 cases of HCC were classified as the well-differentiated type, 50 cases as the moderately differentiated type, and 11 cases as the poorly differentiated type. Immunohistochemical analysis was performed using a rat immunoglobulin G2a monoclonal antibody against the carboxyl terminal region of human MK. In situ hybridization was also performed on 20 HCC samples. RESULTS: We successfully applied this monoclonal antibody against MK to analyze archival paraffin sections. The cancer tissues showed a positive reaction to this antibody, in which there was an intense reaction in their cytoplasm. Approximately one third of the individuals with HCC (26/77) had tumor cells that expressed MK, and these were classified into the following types: moderately differentiated (20/50), well differentiated (3/16), and poorly differentiated (3/11). The in situ hybridization analysis revealed that the signals of MK transcripts were found in the cytoplasm of the cancer cells; the distribution and localization of the MK transcripts' signals determined by in situ hybridization analysis were similar to those obtained by immunohistochemical analysis. CONCLUSIONS: Hepatocellular carcinoma expressed increased MK at the messenger RNA and protein level.