title: Potential Role of CD133 Expression in the Susceptibility of Human Liver Cancer Stem-Like Cells to TRAIL.
abstract: Hepatocellular carcinoma (HCC) is one of the most common malignancies, with a poor prognosis and high recurrence rate. In the present study, we identified CD133, one of the markers of cancer stem cells, as a novel molecular target of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In four human HCC cell lines established from primary HCC tumors, we found that CD133-high human liver cancer stem-like cells (CD133hi) derived from the SNU-475 cell line were highly susceptible to TRAIL compared to other HCC cell lines with a small population of CD133. CD133hi SNU-475 cells showed upregulation of TRAIL receptor DR5 and stemness-related genes such as c-Myc and ABC transporters compared to their CD133-low (CD133lo) cells. Hypersensitivity of CD133hi cells to TRAIL was associated with c-Myc-mediated upregulation of DR5 and downregulation of c-FLIPL in the cells. Knockdown of CD133 expression in CD133hi cells resulted in the downregulation of c-Myc, and depletion of c-Myc caused a decrease in the cell surface expression of DR5 and an increase in the expression of c-FLIPL and, consequently, attenuated TRAIL-induced cytotoxicity and apoptosis of CD133hi cells. These results suggest that TRAIL may provide a new strategy for CD133hi CSCs of HCC-targeted therapies and, potentially, for therapies of other CD133-expressing types of cancer.
authors.affiliation: Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
authors.forename: Su-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Suh-Kyung
authors.initials: SK
authors.lastname: Hyun
authors.forename: Hak-Bong
authors.initials: HB
authors.lastname: Kim
authors.forename: Chi-Dug
authors.initials: CD
authors.lastname: Kang
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000071916:AC133 Antigen; D051017:Apoptosis Regulatory Proteins; C000606023:PROM1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human