Reciprocal co-expression of Fas and Fas ligand in human cholangiocarcinoma.
We have previously characterized the role of Fas in tumorigenesis using two cholangiocarcinoma cell lines expressing high (Fas(H)) and low (Fas(L)) levels of Fas. Here we further characterize Fas ligand (FasL) expression and function in these two cell lines. The Fas(L) cells expressed a high level of FasL, whereas the Fas(H) cells expressed a low level of FasL showing reciprocal expression of Fas and FasL in tumor cells. FasL released from the Fas(L) 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 Fas(L) cells compared to the Fas(H) cells. The inverse activities of Fas and FasL promoter in tumor cells are regulated by NF-kappaB, 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-kappaB 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-kappaB. These findings provide a potential unifying molecular mechanism for modulating tumorigenesis via Fas/FasL expression.
Pan
George
G
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Ahn
Eun-Young
EY
Chen
Yabing
Y
Feng
Gong
G
Reddy
Vishnu
V
Jhala
Nirag C
NC
McDonald
Jay M
JM
D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D015152:Blotting, Northern; D015153:Blotting, Western; D018281:Cholangiocarcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*