title: Pancreatic Tumor Progression Associated With CD133 Overexpression: Involvement of Increased TERT Expression and Epidermal Growth Factor Receptor-Dependent Akt Activation.
abstract: OBJECTIVE
  The aim of this study was to investigate the role of CD133 in pancreatic ductal adenocarcinoma malignancy and its involvement in epidermal growth factor receptor (EGFR) signaling.
  
  
  METHODS
  The effects of CD133 overexpression on cell proliferation, migration, invasiveness, and angiogenesis were investigated in the human pancreatic ductal adenocarcinoma cell line AsPC-1 in vitro and severe combined immunodeficiency xenografts in vivo.
  
  
  RESULTS
  AsPC-1 cells overexpressing CD133 (AsPC-1 CD133 cells) had elevated cell proliferation, tumorigenesis, cell cycle progression, adhesion, migration, and angiogenesis. AsPC-1 CD133 cells displayed increased survival during treatment with chemotherapeutic agents. CD133 overexpression resulted in decreased EGF expression, increased telomerase reverse transcriptase expression, and increased Akt phosphorylation. Immunoprecipitation assays and immunofluorescent labeling studies revealed that CD133 physically interacts with EGFR. The EGFR inhibitor gefitinib was shown to have potent anti-CD133 activity, decreasing the CD133-induced migration of AsPC-1 CD133 cells. Knockdown of CD133 was also observed to inhibit AsPC-1 CD133 cell proliferation, migration, and invasion.
  
  
  CONCLUSIONS
  Our results indicate that CD133-induced cancer stem cell activity may arise from enhanced telomerase reverse transcriptase expression and CD133 ligand-independent EGFR activation to exhibit the cancer stem cell phenotype, promoting cancer stem cell proliferation independent of cytokines, with high metastatic potential and the development of chemoresistance.
authors.affiliation: From the *Institute of Biomedical Sciences, National Sun Yat-Sen University; †Division of Hepatobiliary Pancreatic Surgery, Department of Surgery; and ‡Center for Stem Cell Research, Kaohsiung Medical University Hospital; §National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center; ∥Division of Endocrinology and Metabolism and ¶Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital; and #Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung; **National Institute of Cancer Research, National Health Research Institutes, Tainan; and ††Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
authors.forename: Ching-Chieh
authors.initials: CC
authors.lastname: Weng
authors.forename: Kung-Kai
authors.initials: KK
authors.lastname: Kuo
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Su
authors.forename: Pi-Jung
authors.initials: PJ
authors.lastname: Hsiao
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Deng-Chyang
authors.initials: DC
authors.lastname: Wu
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.forename: Kuang-Hung
authors.initials: KH
authors.lastname: Cheng
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase; D000077156:Gefitinib; D005472:Fluorouracil