title: Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma.
abstract: Purpose:Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere-forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.Experimental Design and Results:We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos-overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial-mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.Conclusions:Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment.Clin Cancer Res; 23(12); 3120-8. ©2016 AACR.
authors.affiliation: Department of Pathology, Saint Louis University, St. Louis, Missouri.
authors.forename: Naoshad
authors.initials: N
authors.lastname: Muhammad
authors.affiliation: Department of Pathology, Saint Louis University, St. Louis, Missouri.
authors.forename: Sourav
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Pathology, Saint Louis University, St. Louis, Missouri.
authors.forename: Robert
authors.initials: R
authors.lastname: Steele
authors.affiliation: Department of Pathology, Saint Louis University, St. Louis, Missouri.
authors.forename: Nancy
authors.initials: N
authors.lastname: Phillips
authors.affiliation: Department of Pathology, Saint Louis University, St. Louis, Missouri. rayrb@slu.edu.|Cancer Center, Saint Louis University, St. Louis, Missouri.
authors.forename: Ratna B
authors.initials: RB
authors.lastname: Ray
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D009363:Neoplasm Proteins; D016760:Proto-Oncogene Proteins c-fos