We have previously characterized the role of Fas in tumorigenesis using two cholangiocarcinoma cell lines expressing high (FasH) and low (FasL) levels of Fas. Here we further characterize Fas ligand (FasL) expression and function in these two cell lines. The FasL cells expressed a high level of FasL, whereas the FasH cells expressed a low level of FasL showing reciprocal expression of Fas and FasL in tumor cells. FasL released from the FasL cells is capable of inducing apoptosis of lymphocytes, which is blocked by neutralizing Fas antibody. To study the underlying mechanism for the reciprocal expression of Fas and FasL, we examined the activities of both the Fas and FasL promoters. The activity of the Fas promoter is suppressed and the activity of the FasL promoter is stimulated in the FasL cells compared to the FasH cells. The inverse activities of Fas and FasL promoter in tumor cells are regulated by NF-κB, which inhibits Fas expression and increases FasL expression through binding to their respective promoters. The inverse expression of Fas and FasL in tumor cells is partially reversed by an NF-κB inhibitor. In conclusion, human cholangiocarcinoma cells reciprocally co-express functional Fas and FasL, which are the result of the activities of the Fas and FasL promoters being regulated by NF-κB. These findings provide a potential unifying molecular mechanism for modulating tumorigenesis via Fas/FasL expression.

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