title: Concomitant targeting of multiple key transcription factors effectively disrupts cancer stem cells enriched in side population of human pancreatic cancer cells.
abstract: BACKGROUND
  A major challenge in the treatment of pancreatic ductal adenocarcinoma is the failure of chemotherapy, which is likely due to the presence of the cancer stem cells (CSCs).
  
  
  OBJECTIVE
  To identify side population (SP) cells and characterize s-like properties in human pancreatic cancer cell lines (h-PCCLs) and to exploit the efficacy of concomitant targeting of multiple key transcription factors governing the stemness of pancreatic CSCs in suppressing CSC-like phenotypes.
  
  
  METHODS
  Flow cytometry and Hoechst 33342 DNA-binding dye efflux assay were used to sort SP and non-SP (NSP) cells from three h-PCCLs: PANC-1, SW1990, and BxPc-3. The self-renewal ability, invasiveness, migration and drug resistance of SP cells were evaluated. Expression of CSC marker genes was analyzed. Tumorigenicity was assessed using a xenograft model in nude mice. Effects of a complex decoy oligonucleotide (cdODN-SCO) designed to simultaneously targeting Sox2, Oct4 and c-Myc were assessed.
  
  
  RESULTS
  CSCs were enriched in the side proportion (SP) cells contained in the h-PCCLs and they possessed aggressive growth, invasion, migration and drug-resistance properties, compared with NSP cells. SP cells overexpressed stem cell markers CD133 and ALDH1, pluripotency maintaining factors Nanog, Sox2 and Oct4, oncogenic transcription factor c-Myc, signaling molecule Notch1, and drug resistant gene ABCG2. Moreover, SP cells consistently demonstrated significantly greater tumorigenicity than NSP cells in xenograft model of nude mice. CdODN-SOC efficiently suppressed all CSC properties and phenotypes, and minimized the tumorigenic capability of the SP cells and the resistance to chemotherapy. By comparison, the negative control failed to do so.
  
  
  CONCLUSIONS
  The findings indicate that targeting the key genes conferring the stemness of CSCs can efficiently eliminate CSC-like phenotypes, and thus may be considered a new approach for cancer therapy. Specifically, the present study establishes the combination of Sox2/Oct4/c-Myc targeting as a potential anti-pancreatic cancer agent worthy of further studies in preclinical settings.
authors.affiliation: Department of Hepatobiliary Surgery, Cancer Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Wang
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.forename: Benxin
authors.initials: B
authors.lastname: Hou
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Huimin
authors.initials: H
authors.lastname: Jia
authors.forename: Haijun
authors.initials: H
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Yan
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Ding
authors.forename: Chao
authors.initials: C
authors.lastname: Yi
authors.lastname: Hai Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D058985:Side-Population Cells; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009841:Oligonucleotides; D014157:Transcription Factors
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