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Cholangiocarcinoma is an aggressive malignant tumor originating from intrahepatic or extrahepatic bile ducts. Its malignant phenotypes may be assumed by cancer stem cells ( CSC ). Here, we demonstrate that  CD 274 ( PD ‐L1), known as an immunomodulatory ligand, has suppressive effects on  CSC ‐related phenotypes of cholangiocarcinoma. Using two human cholangiocarcinoma cell lines,  RBE  and Hu CCT 1, we attempted to isolate the  CD 274 low  and  CD 274 high  cells from each cell line, and xenografted them into immunodeficient  NOD ⁄scid⁄γcnull ( NOG ) mice. We found that the  CD 274 low  cells isolated from both  RBE  and Hu CCT 1 are highly tumorigenic in  NOG  mice compared with  CD 274 high  cells. Furthermore, the  CD 274 low  cells possess several  CSC ‐related characteristics, such as high  aldehyde dehydrogenase (ALDH)  activity, reduced reactive oxygen species production and a dormant state in the cell cycle. Furthermore, depletion of CD274 expression by sh RNA  in  RBE  cells enhances their tumorigenicity and increases  ALDH  activity. These findings are compatible with our observation that clinical cholangiocarcinoma specimens are classified into low and high groups for  CD 274 expression, and the  CD 274 low group shows poorer prognosis when compared with the  CD 274 high group. These results strongly suggest that  CD 274 has a novel function in the negative regulation of  CSC ‐related phenotypes in human cholangiocarcinoma, which is distinct from its immunomodulatory actions.

Suppressive expression of CD 274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma