Application of Ninjurin, a novel adhesion molecule, to diagnosis and therapeutics of primary hepatocellular carcinoma

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Ninjurin is a novel protein that is up regulated after nerve injury. It is reported that Ninjurin demonstrates properties of a homophilic adhesion molecule and plays an important role in neurite regeneration. We found that, in rat liver regeneration model, Ninjurin expression was enhanced in the differentiation phase after proliferation phase. In addition, expression of Ninjurin was decreased in cancerous lesion of human hepatocellular carcinoma tissue. To determine the biological consequence of Ninjurin expression in human hepatocytes, we established Huh7 constitutively over-expressing Ninjurin protein and performed the following examinations, (1) analysis of growth curve with hemocytometer, (2) flow cytometric analysis of cell cycle, (3) Western blot analysis of cell cycle related protein. Proliferation of Huh7 cells over-expressing Ninjurin was inhibited compared to that of control cells. Cell cycle was arrested at G1/S checkpoints on a fluorescence-activated cell sorter, and the fraction of S phase declined from 45% to 25%. The arrest induced by Ninjurin was accompanied by the accumulation of p21 expression level and decreases of Cdk2, Cdk4, Cdk6 expression levels. But there is no change in the expression of Cdk inhibitor p16, p27, cyclin D1, and Cyclin E expression. In contrast, expression of Cyclin A was slightly decreased. In this way, Ninjurin induces both down-regulation of cell cycle activators and up-regulation of cell cycle inhibitor, followed by inhibition of cell growth. These observations suggest that the low expression of Ninjurin in HCC may contribute to growth of hepatoma-cells. Therefore, induction of Ninjurin can be expected to suppress growth of hepatoma, which may provide a novel strategy for hepatocellular carcinoma.