title: Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma.
abstract: Notch1 is associated with the initiation and progression of various solid tumors. However, the exact role of Notch1 expression in head and neck squamous cell carcinoma (HNSCC) remain unclear. We created cells ectopically expressing notch intracellular domain (NICD) from previously established HNSCC cells and examined self-renewal capacity and stem cell markers' expression compared with control cells. In addition, we knocked Notch1 down in primary spheres obtained from HNSCC tumor tissue and assessed the attenuation of stemness-associated traits in these cells in vitro and in vivo. Furthermore, we examined clinical relevance of Notch1 expression in HNSCC patients. Constitutive activation of NICD promoted the self-renewal capacity of HNSCC cells by activating sphere formation and increased the expression of stem cell markers such as Oct4, Sox2, and CD44. In contrast, Notch1 knockdown in primary HNSCC cancer stem cells (CSCs) attenuated CSC traits and augmented the chemosensitizing effects of cisplatin along with the decreased expression of almost all of ABC transporter genes. In addition, Notch1 knockdown in HNSCC CSCs inhibited tumor formation and increased survival of mice in a xenograft model. Also, Notch1 acted upstream of canonical Wnt signaling in HNSCC cells. Finally, elevated Notch1 expression is associated with poor prognosis in patients with HNSCC. In conclusion, Notch1 may be a critical regulator of stemness in HNSCC cells, and inactivation of this pathway could be a potential targeted approach for the treatment of HNSCC.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Medical Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sung I
authors.initials: SI
authors.lastname: Do
authors.affiliation: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Hyun J
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Cancer Research Institute, Research Institute for Medical Science, Chungnam National University College of Medicine, Daejeon, Korea.
authors.forename: Bon S
authors.initials: BS
authors.lastname: Koo
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute of Medical Science, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Young C
authors.initials: YC
authors.lastname: Lim
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D002945:Cisplatin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; C116614:ABCG2 protein, human; C497761:NOTCH1 protein, human