Department of Oral and Maxillofacial Surgery, University Hospital Tübingen, Osianderstrasse 2-8, 72076 Tuebingen, Germany.
Eur J Cancer. 2012 Nov;48(17):3186-97. doi: 10.1016/j.ejca.2012.05.027. Epub 2012 Jul 10.
The vast majority of oral cancers are squamous cell carcinomas (OSCC). The effectiveness of adjuvant cytostatic chemotherapy for OSCC is frequently restricted due to an inducible cellular mechanism called multidrug resistance (MDR) and a putative cancer stem cell (CSC) compartment in human carcinogenesis expressing multidrug efflux pumps. The novel human ATP-binding cassette (ABC) transporter ABCB5 [subfamily B (MDR/TAP) member 5] acts as an energy-dependent drug efflux transporter and marks tumour cells of a putative CSC compartment. However, to date, there is no link between ABCB5 expression and OSCC.
Expression of ABCB5 was analysed in OSCC specimen (n=191) and cancer cell lines (BICR3, BICR56) by immunohistochemistry, real-time polymerase chain reaction (RT-PCR) analysis and western blotting. Scanned images were digitally analysed using ImageJ and the immunomembrane plug-in. ABCB5 expression on protein level was correlated with clinical characteristics and impact on survival. ABCB5 was co-labelled with CD44 in immunohistochemical and immunofluorescence double labelling experiments. Expression subgroups were identified by receiver operating characteristics (ROC) analysis.
High ABCB5 expression was significantly associated with tumour progression and recurrence of the tumour. Multivariate analysis demonstrated high ABCB5 expression as an independent prognostic factor (p=0.0004). Immunohistochemical and immunofluorescence double labelling experiments revealed ABCB5 expression by CD44+ cancer cells. ABCB5 specificity was confirmed by western blot and RT-PCR analysis.
For the first time, this study provides evidence that ABCB5 expression in OSCC might be associated with tumour formation, metastasis and a putative CSC compartment. One of the principal mechanisms for protecting putative cancer stem cells is through the expression of multifunctional efflux transporters from the ABC gene family, like ABCB5. This provides one mechanism in which putative cancer stem cells could survive and may lead to tumour relapse. Knowledge of expression profiles of ABC transporters and other genes involved in MDR will likely help therapeutic optimisation for cancer patients in clinic. However, this hypothesis requires further in vitro and in vivo studies.
绝大多数口腔癌为鳞状细胞癌（OSCC）。由于诱导性细胞机制（称为多药耐药性（MDR））和人类癌发生中表达多药外排泵的假定癌症干细胞（CSC）隔室，辅助细胞抑制化疗对 OSCC 的有效性经常受到限制。新型人 ATP 结合盒（ABC）转运蛋白 ABCB5[亚家族 B（MDR/TAP）成员 5] 作为一种能量依赖性药物外排转运蛋白起作用，并标记假定 CSC 隔室的肿瘤细胞。然而，迄今为止，尚无 ABCB5 表达与 OSCC 之间的联系。
通过免疫组织化学，实时聚合酶链反应（RT-PCR）分析和蛋白质印迹分析，分析了 OSCC 标本（n=191）和癌细胞系（BICR3，BICR56）中的 ABCB5 表达。使用 ImageJ 和免疫膜插件对扫描图像进行数字分析。蛋白质水平上的 ABCB5 表达与临床特征和生存影响相关。在免疫组织化学和免疫荧光双重标记实验中，ABC B5 与 CD44 共标记。通过接收者操作特征（ROC）分析确定表达亚组。
高 ABCB5 表达与肿瘤进展和肿瘤复发显着相关。多变量分析表明，高 ABCB5 表达是独立的预后因素（p=0.0004）。免疫组织化学和免疫荧光双重标记实验显示 ABCB5 表达由 CD44+癌细胞。通过蛋白质印迹和 RT-PCR 分析证实了 ABCB5 的特异性。
这项研究首次提供了证据，表明 ABCB5 在 OSCC 中的表达可能与肿瘤形成，转移和假定的 CSC 隔室有关。保护假定的癌症干细胞的主要机制之一是通过表达 ABC 基因家族的多功能外排转运蛋白，如 ABCB5。这提供了一种假设，即假定的癌症干细胞可以存活，并可能导致肿瘤复发。对 ABC 转运蛋白和其他参与 MDR 的基因的表达谱的了解可能有助于优化癌症患者的临床治疗。但是，该假设需要进一步的体外和体内研究。
