Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation
Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation
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DOI：
10.1038/onc.2017.303
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发表时间：
2018-01-04
期刊：
影响因子：
8
通讯作者：
Wu, M-H
中科院分区：
文献类型：
--
作者：
Chiang, W-F;Cheng, T-M;Wu, M-H
异常蛋白糖基化可能是影响癌症进展和转移的癌细胞的独特表面标志物，因为糖基化可以调节膜蛋白折叠，从而改变受体活化并改变抗体（Ab）识别的表位暴露。癌胚抗原相关细胞粘附分子6（CEACAM 6）是一种糖磷酸肌醇锚定蛋白，是一种高度糖基化的肿瘤抗原。然而，CEACAM 6糖基化的临床意义和生物学效应尚未在癌症中得到解决。我们最近从免疫大羊驼文库中开发了抗CEACAM 6 Ab（TMU），其可以被工程化为单结构域（sd）Ab或重链（HC）Ab。与常规抗体相比，TMU HCAb特异性识别糖基化CEACAM 6。使用TMU HCAb，我们发现糖基化CEACAM 6是与早期OSCC（口腔鳞状细胞癌）患者复发相关的肿瘤标志物。CEACAM 6通过与表皮生长因子（EGF）受体（EGFR）相互作用并增强EGFR活化、聚集和细胞内信号级联，促进OSCC细胞的侵袭、迁移、细胞骨架重排和转移。这些功能由N-乙酰葡糖胺基转移酶5（MGAT 5）调节，MGAT 5介导CEACAM 6的Asn（256）（N256）处的N-糖基化。最后，TMU sdAb和HCAb处理抑制CEACAM 6过表达细胞中的迁移、侵袭和EGF诱导的信号传导。总之，CEACAM 6的复杂N-糖基化对于EGFR信号传导的OSCC侵袭和转移至关重要。用TMU sdAb或TMU HCAb靶向糖基化的CEACAM 6可能是OSCC的可行疗法。
Aberrant protein glycosylation could be a distinct surface-marker of cancer cells that influences cancer progression and metastasis because glycosylation can regulate membrane protein folding which alters receptor activation and changes epitope exposure for antibody (Ab) recognition. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a glycophosphoinositol-anchored protein, is a heavily glycosylated tumor antigen. However, the clinical significance and biological effect of CEACAM6 glycosylation has not been addressed in cancers. We recently developed an anti-CEACAM6 Ab (TMU) from an immune llama library which can be engineered to a single-domain (sd)Ab or a heavy-chain (HC)Ab. The TMU HCAb specifically recognized glycosylated CEACAM6 compared to the conventional antibodies. Using the TMU HCAb, we found that glycosylated CEACAM6 was a tumor marker associated with recurrence in early-stage OSCC (oral squamous cell carcinoma) patients. CEACAM6 promoted OSCC cell invasion, migration, cytoskeletal rearrangement, and metastasis via interaction with epidermal growth factor (EGF) receptor (EGFR) and enhancing EGFR activation, clustering and intracellular signaling cascades. These functions were modulated by N-acetylglucosaminyltransferase 5 (MGAT5) which mediated N-glycosylation at Asn(256) (N256) of CEACAM6. Finally, the TMU sdAb and HCAb treatment inhibited the migration, invasion and EGF-induced signaling in CEACAM6-overexpressing cells. In conclusion, the complex N-glycosylation of CEACAM6 is critical for EGFR signaling of OSCC invasion and metastasis. Targeting glycosylated CEACAM6 with the TMU sdAb or TMU HCAb could be a feasible therapy for OSCC.