title: Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy.
abstract: Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy.
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Takuya
authors: T
authors: Asano
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Yoshihiko
authors: Y
authors: Hirohashi
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Toshihiko
authors: T
authors: Torigoe
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Tasuku
authors: T
authors: Mariya
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Ryota
authors: R
authors: Horibe
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Takafumi
authors: T
authors: Kuroda
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Yuta
authors: Y
authors: Tabuchi
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Hiroshi
authors: H
authors: Saijo
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Kazuyo
authors: K
authors: Yasuda
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.|Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Masahito
authors: M
authors: Mizuuchi
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Akari
authors: A
authors: Takahashi
authors: Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Hiroko
authors: H
authors: Asanuma
authors: Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Tadashi
authors: T
authors: Hasegawa
authors: Obsterics and Gynecology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Tsuyoshi
authors: T
authors: Saito
authors: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors: Noriyuki
authors: N
authors: Sato
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: C456540:CTCFL protein, human; D004268:DNA-Binding Proteins; D020033:Protein Isoforms
keywords: BORIS; CTL; cancer stem cells; cervical cancer; peptide vaccine