title: Ectopic overexpression of CD133 in HNSCC makes it resistant to commonly used chemotherapeutics.
abstract: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in the world. Resistance to cytotoxic chemotherapy is a major cause of mortality in patients with HNSCC. A small subset of cancer cells called cancer stem cells (CSCs) may be key contributors to drug resistance and tumor recurrence in HNSCC. The aim of this study was to determine whether CD133, which maintains properties of CSCs, promotes chemoresistance by arresting cell cycle transition and reducing apoptosis in HNSCC cells. CD133 overexpression was examined in KB cells, and colony forming and aldehyde dehydrogenase activity assays were performed. To investigate the role of CD133 in chemoresistance, cell death was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Diff-Quick, flow cytometry, and western blot of apoptosis-related protein expression in fluorouracil (5-FU)- or cisplatin-treated cells. In addition, microarray and related protein expression assessments were performed to investigate the mechanism of chemoresistance against 5-FU and cisplatin in KB cells. Moreover, chemoresistance against 5-FU or cisplatin in a KB-inoculated mouse model was analyzed by hematoxylin and eosin staining, immunohistochemical study of CD133, and immunofluorescence of tumor tissue. In this study, we demonstrate that ectopic overexpression of CD133 significantly promotes properties of stemness in KB cell lines. Furthermore, CD133 promotes chemoresistance by arresting transition of the cell cycle and reducing apoptosis, which results in inhibition of tumor growth in 5-FU- or cisplatin-injected mouse tumor model. Taken together, our findings show that elevated levels of CD133 lead to HNSCC chemoresistance through increased stemness and cell cycle arrest.
authors.affiliation: 1 Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, Korea.
authors.forename: Junyoung
authors.initials: J
authors.lastname: Lee
authors.affiliation: 2 Department of Premedical Science, College of Medicine, Chosun University, Gwangju, Korea.
authors.forename: Mineon
authors.initials: M
authors.lastname: Park
authors.affiliation: 2 Department of Premedical Science, College of Medicine, Chosun University, Gwangju, Korea.
authors.forename: Youngjong
authors.initials: Y
authors.lastname: Ko
authors.affiliation: 2 Department of Premedical Science, College of Medicine, Chosun University, Gwangju, Korea.
authors.forename: Bora
authors.initials: B
authors.lastname: Kim
authors.affiliation: 3 Department of Oral Pathology, School of Dentistry, Chonnam National University, Gwangju, Korea.
authors.forename: Okjoon
authors.initials: O
authors.lastname: Kim
authors.affiliation: 4 Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Hoon
authors.initials: H
authors.lastname: Hyun
authors.affiliation: 1 Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, Korea.
authors.forename: DongHwi
authors.initials: D
authors.lastname: Kim
authors.affiliation: 1 Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, Korea.
authors.forename: HongMoon
authors.initials: H
authors.lastname: Sohn
authors.affiliation: 1 Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, Korea.
authors.forename: Young Lae
authors.initials: YL
authors.lastname: Moon
authors.affiliation: 1 Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, Korea.|2 Department of Premedical Science, College of Medicine, Chosun University, Gwangju, Korea.
authors.forename: Wonbong
authors.initials: W
authors.lastname: Lim
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D002945:Cisplatin / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007624:KB Cells; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human; D011993:Recombinant Fusion Proteins; D002945:Cisplatin; D005472:Fluorouracil
keywords: 5-FU; CD133; cancer stem cell; chemoresistance; cisplatin