title: Osteopontin-integrin α(v)β(3) axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma.
abstract: Clinical applications of a chemotherapeutic agent, 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) have been limited because of drug resistance. This study aimed to identify novel mechanisms of 5-FU resistance. Here we found increased osteopontin (OPN) gene expression in OSCC tissues with resistance to 5-FU-based chemoradiotherapy. OPN overexpression in OSCC cells led to 5-FU resistance and abrogated the prosurvival effect of the drug in a mouse xenograft model. OPN-induced 5-FU resistance required integrin αvβ3. Targeting integrin αvβ3 reversed the resistance in a 5-FU-resistant clone highly expressing OPN. Our data suggest that the OPN-integrin αvβ3 axis is crucial for 5-FU resistance in OSCC.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Japan. Electronic address: satoru.shinriki@gmail.com.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.affiliation: Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pharmacy, Kumamoto University Hospital, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Jono
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Ueda
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Jianying
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ota
authors.affiliation: Department of Oral and Maxillofacial Surgery, Kumamoto City Hospital, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Ota
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamashita
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Akimitsu
authors.initials: A
authors.lastname: Hiraki
authors.affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D039302:Integrin alphaVbeta3; D053495:Osteopontin; D005472:Fluorouracil
keywords: Cancer; Chemotherapeutic agents; Drug resistance; Osteopontin overexpression