title: CD133/Src axis mediates tumor initiating property and epithelial-mesenchymal transition of head and neck cancer.
abstract: BACKGROUND
  Head and Neck squamous cell carcinoma (HNSCC) is a human lethal cancer with clinical, pathological, phenotypical and biological heterogeneity. Caner initiating cells (CICs), which are responsible for tumor growth and coupled with gain of epithelial-mesenchymal transition (EMT), have been identified. Previously, we enriched a subpopulation of head and neck cancer initiating cells (HN-CICs) with up-regulation of CD133 and enhancement of EMT. Others demonstrate that Src kinase interacts with and phosphorylates the cytoplasmic domain of CD133. However, the physiological function of CD133/Src signaling in HNSCCs has not been uncovered.
  
  
  RESULTS
  Herein, we determined the critical role of CD133/Src axis modulating stemness, EMT and tumorigenicity of HNSCC and HN-CICs. Initially, down-regulation of CD133 significantly reduced the self-renewal ability and expression of stemness genes, and promoted the differentiation and apoptotic capability of HN-CICs. Additionally, knockdown of CD133 in HN-CICs also lessened both in vitro malignant properties including cell migration/cell invasiveness/anchorage independent growth, and in vivo tumor growth by nude mice xenotransplantation assay. In opposite, overexpression of CD133 enhanced the stemness properties and tumorigenic ability of HNSCCs. Lastly, up-regulation of CD133 increased phosphorylation of Src coupled with EMT transformation in HNSCCs, on the contrary, silence of CD133 or treatment of Src inhibitor inversely abrogated above phenotypic effects, which were induced by CD133 up-regulation in HNSCCs or HN-CICs.
  
  
  CONCLUSIONS
  Our results suggested that CD133/Src signaling is a regulatory switch to gain of EMT and of stemness properties in HNSCC. Finally, CD133/Src axis might be a potential therapeutic target for HNSCC by eliminating HN-CICs.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yu-Syuan
authors.initials: YS
authors.lastname: Chen
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Wu
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Lin
authors.forename: Tsung-Hsien
authors.initials: TH
authors.lastname: Chuang
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000201:enzymology / Q000473:pathology; D000077195:Squamous Cell Carcinoma of Head and Neck; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019061:src-Family Kinases