RRC ID 44990
Author Tamai K, Nakamura M, Mizuma M, Mochizuki M, Yokoyama M, Endo H, Yamaguchi K, Nakagawa T, Shiina M, Unno M, Muramoto K, Sato I, Satoh K, Sugamura K, Tanaka N.
Title Suppressive expression of CD274 increases tumorigenesis and cancer stem cell phenotypes in cholangiocarcinoma.
Journal Cancer Sci
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.
Volume 105(6)
Pages 667-74
Published 2014-6-1
DOI 10.1111/cas.12406
PMID 24673799
PMC PMC4317902
MeSH Aldehyde Dehydrogenase / metabolism Animals B7-H1 Antigen / genetics B7-H1 Antigen / metabolism* Bile Duct Neoplasms / enzymology Bile Duct Neoplasms / genetics Bile Duct Neoplasms / pathology* Bile Ducts, Intrahepatic / pathology* Biomarkers, Tumor / genetics Biomarkers, Tumor / metabolism* Carcinogenesis / genetics* Cell Cycle Cell Line, Tumor Cholangiocarcinoma / enzymology Cholangiocarcinoma / genetics Cholangiocarcinoma / pathology* Humans Immunomodulation / genetics Mice Mice, Inbred NOD Mice, SCID Neoplastic Stem Cells / cytology* Phenotype Prognosis RNA Interference RNA, Small Interfering Reactive Oxygen Species / metabolism Tretinoin / analysis Xenograft Model Antitumor Assays
IF 4.966
Times Cited 22
Human and Animal Cells RBE(RCB1292) HuCCT1(RCB1960)