title: Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling.
abstract: BACKGROUND
  Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.
  
  
  RESULTS
  Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (memGRP78+) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.
  
  
  CONCLUSIONS
  In summary, memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.
authors.affiliation: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Wu
authors.forename: Chia-Ing
authors.initials: CI
authors.lastname: Jan
authors.forename: Yeou-Guang
authors.initials: YG
authors.lastname: Tsay
authors.forename: Yau-Hua
authors.initials: YH
authors.lastname: Yu
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Huang
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Lin
authors.forename: Chung-Ji
authors.initials: CJ
authors.lastname: Liu
authors.forename: Yu-Syuan
authors.initials: YS
authors.lastname: Chen
authors.forename: Jeng-Fan
authors.initials: JF
authors.lastname: Lo
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D015398:Signal Transduction
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse