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.
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.
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DOI：
10.18632/oncotarget.7165
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发表时间：
2016-03-08
期刊：
影响因子：
--
通讯作者：
Sato N
中科院分区：
文献类型：
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作者：
Asano T;Hirohashi Y;Torigoe T;Mariya T;Horibe R;Kuroda T;Tabuchi Y;Saijo H;Yasuda K;Mizuuchi M;Takahashi A;Asanuma H;Hasegawa T;Saito T;Sato N
宫颈癌是世界范围内女性癌症死亡的主要原因。宫颈癌干细胞样细胞（CSCs）/癌症起始细胞（CIC）对常规放疗和化疗具有抗性，并且CSCs/CIC被认为是复发的原因。因此，根除CSC/CIC对于治愈宫颈癌至关重要。在这项研究中，我们通过球体培养分离宫颈CSC/CIC，并且我们鉴定了在宫颈CSC/CIC中表达的癌症睾丸（CT）抗原CTCFL/BORIS。BORIS有23种mRNA亚型，分为6个亚家族（sfs），它们编码17种不同的BORIS肽。BORIS sf 1和sf 4在CSC/CIC和非CSC/CIC中表达，而BORIS sf6仅在CSC/CIC中表达。与对照细胞相比，BORIS sf6在宫颈癌细胞中的过表达增加了球体形成和肿瘤起始能力，而BORIS sf 1和BORIS sf 4的过表达仅导致轻微增加。因此，BORIS sf6是宫颈CSC/CIC特异性亚家族，在维持宫颈CSC/CIC中起作用。BORIS sf6含有一个特异性的C-末端结构域（C34），我们鉴定了由BORIS sf6编码的人类白细胞抗原（HLA）-A2限制性抗原肽BORIS C34_24（9）。BORIS C34_24（9）特异性细胞毒性T细胞（CTL）克隆显示出对BORIS sf6过表达宫颈癌细胞的细胞毒性。此外，CTL克隆显著抑制CaSki细胞的球体形成。总之，结果表明CT抗原BORIS sf6在宫颈CSC/CIC中特异性表达，BORIS sf6在维持CSC/CIC中具有作用，并且BORIS C34_24（9）肽是宫颈CSC/CIC靶向免疫治疗的有希望的候选物。
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.