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ABSTRACT: Background and aims: The nuclear factor of the activated T cell (NFAT) family was primarily recognized for its central role in T lymphocyte activation. Recent evidence showed that NFAT isoforms participate in the regulation of genes related to cell proliferation and differentiation in epithelial malignancies. Here, we investigated the expression and activation of the calcineurin/NFAT transcription pathway and its role in hepatocellular carcinoma (HCC) proliferation. Methods: Expression of NFATc1 and calcineurin proteins was examined by immunohistochemical analyses in 76 human HCC samples. The cellular NFAT activation and distribution in HepG2 cells were analyzed by immunofluorescence and western blot analyses. After NFATc1 expression was knocked down by NFATc1-specific siRNA, we analyzed its implications in cell cycle progression and growth by MTT and flow cytometry. The impact of calcineurin/NFAT signaling on protein expression of c-myc and cox-2 were performed by western blot analyses. Results: NFATc1 is significantly overexpressed in HCC. The regulation of calcineurin activity by ionomycin or cyclosporin A caused rapid nuclear import or export of NFATc1 in HepG2 cells. NFATc1 knock-down led to a significant reduction in proliferation rates and cell cycle arrest at G1 phase. The expression of c-myc and cox-2 was decreased in the NFATc1 knock-down HepG2 cells. Ionomycin increased c-myc and cox-2 expression in HepG2 cells, but not in siNFATc1 HepG2 cells. Conclusion: The calcineurin/NFATc1 signal is overexpressed and active in HCC. It may enhance the proliferative potential of HepG2 cells through transcriptional activation of the c-myc and cox-2 oncogenes.