title: Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma.
abstract: 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 CD274 (PD-L1), known as an immunomodulatory ligand, has suppressive effects on CSC-related phenotypes of cholangiocarcinoma. Using two human cholangiocarcinoma cell lines, RBE and HuCCT1, we attempted to isolate the CD274(low) and CD274(high) cells from each cell line, and xenografted them into immunodeficient NOD⁄scid⁄γcnull (NOG) mice. We found that the CD274(low) cells isolated from both RBE and HuCCT1 are highly tumorigenic in NOG mice compared with CD274(high) cells. Furthermore, the CD274(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 shRNA 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 CD274 expression, and the CD274 low group shows poorer prognosis when compared with the CD274 high group. These results strongly suggest that CD274 has a novel function in the negative regulation of CSC-related phenotypes in human cholangiocarcinoma, which is distinct from its immunomodulatory actions.
authors.affiliation: Division of Cancer Biology and Therapeutics, Miyagi Cancer Center Research Institute, Natori, Japan; Department of Cancer Science, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.forename: Mao
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masamichi
authors.initials: M
authors.lastname: Mizuma
authors.forename: Mai
authors.initials: M
authors.lastname: Mochizuki
authors.forename: Misa
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Endo
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Michiaki
authors.initials: M
authors.lastname: Unno
authors.forename: Koji
authors.initials: K
authors.lastname: Muramoto
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010641:Phenotype; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D014212:Tretinoin / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014212:Tretinoin; D000444:Aldehyde Dehydrogenase
keywords: Aldehyde dehydrogenase; cell cycle; dormancy; prognosis; tumorigenicity