title: Focal overexpression of CEACAM6 contributes to enhanced tumourigenesis in head and neck cancer via suppression of apoptosis.
abstract: BACKGROUND
  Overexpression of CEACAM6 has been reported for a number of malignancies. However, the mechanism of how CEACAM6 contributes to cancer formation and its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. Therefore, we examined the role of CEACAM6 in head and neck squamous cell carcinoma (HNSCC).
  
  
  METHODS
  CEACAM6 expression was examined in normal squamous epithelia as well as a number of patient HNSCC samples and tumours derived from HNSCC cell lines injected into NOD/SCID mice. CEACAM6 expression was manipulated in HNSCC cell lines by shRNA-mediated CEACAM6 knockdown or virally-delivered overexpression of CEACAM6. The role of CEACAM6 in tumour growth and chemotherapeutic sensitivity was then assessed in vivo and in vitro respectively.
  
  
  RESULTS
  CEACAM6 expression was significantly increased in highly tumourigenic HNSCC cell lines when compared to poorly tumourigenic HNSCC cell lines. Moreover, HNSCC patient tumours demonstrated focal expression of CEACAM6. Functional investigation of CEACAM6, involving over-expression and knock down studies, demonstrated that CEACAM6 over-expression could enhance tumour initiating activity and tumour growth via activation of AKT and suppression of caspase-3 mediated cell death.
  
  
  CONCLUSIONS
  We report that CEACAM6 is focally overexpressed in a large fraction of human HNSCCs in situ. We also show that over-expression of CEACAM6 increases tumour growth and tumour initiating activity by suppressing PI3K/AKT-dependent apoptosis of HNSCC in a xenotransplant model of HNSCC. Finally, our studies indicate that foci of CEACAM6 expressing cells are selectively ablated by treatment of xenotransplant tumours with pharmacological inhibitors of PI3K/AKT in vivo.
authors.affiliation: University of Queensland Diamantina Institute, Epithelial Pathobiology Group, Princess Alexandra Hospital, Queensland, Australia.
authors.forename: Sarina
authors.initials: S
authors.lastname: Cameron
authors.forename: Lilia Merida
authors.initials: LM
authors.lastname: de Long
authors.forename: Mehlika
authors.initials: M
authors.lastname: Hazar-Rethinam
authors.forename: Eleni
authors.initials: E
authors.lastname: Topkas
authors.forename: Liliana
authors.initials: L
authors.lastname: Endo-Munoz
authors.forename: Andrew
authors.initials: A
authors.lastname: Cumming
authors.forename: Orla
authors.initials: O
authors.lastname: Gannon
authors.forename: Alexander
authors.initials: A
authors.lastname: Guminski
authors.forename: Nicholas
authors.initials: N
authors.lastname: Saunders
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D058851:GPI-Linked Proteins / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; C504117:CEACAM6 protein, human