Open AccessSuppressive expression of CD 274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma
Author(s) -
Tamai Keiichi,
Nakamura Mao,
Mizuma Masamichi,
Mochizuki Mai,
Yokoyama Misa,
Endo Hiroyuki,
Yamaguchi Kazunori,
Nakagawa Takayuki,
Shiina Masaaki,
Unno Michiaki,
Muramoto Koji,
Sato Ikuro,
Satoh Kennichi,
Sugamura Kazuo,
Tanaka Nobuyuki
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12406
Subject(s) - cancer stem cell , carcinogenesis , cancer research , aldehyde dehydrogenase , phenotype , stem cell , cell culture , cancer cell , cancer , biology , cell , microbiology and biotechnology , gene , biochemistry , genetics
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.