The predicted 129-amino acid FN14 protein, which shares 82% amino acid identity with the mouse sequence, contains a signal peptide, an extracellular domain, a membrane-anchoring domain, and a cytoplasmic domain. Northern blot analysis detected increased FN14 expression in response to FGF1, calf serum, or phorbol ester stimulation of human quiescent fibroblasts in vitro. A 1.2-kb FN14 transcript was expressed at high levels in heart, placenta, and kidney, at intermediate levels in lung, skeletal muscle, and pancreas, and at low levels in brain and liver. In addition, elevated FN14 expression was found in human liver cancer cell lines and hepatocellular carcinoma specimens. Expression of mouse Fn14 was upregulated in hepatocellular carcinoma nodules that develop in 2 different transgenic mouse models of hepatocarcinogenesis.