Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) promotes EGF receptor signaling of oral squamous cell carcinoma metastasis via the complex N-glycosylation
Journal
Oncogene
Journal Volume
37
Journal Issue
1
Pages
116
Date Issued
2018
Author(s)
Chiang, W.-F.
Cheng, T.-M.
Chang, C.-C.
Changou, C.A.
Chang, T.-H.
Lee, K.-H.
Wu, S.-Y.
Chen, Y.-F.
Chuang, K.-H.
Shieh, D.-B.
Chen, Y.-L.
Tu, C.-C.
Tsui, W.-L.
Wu, M.-H.
Abstract
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.
SDGs
Other Subjects
carcinoembryonic antigen related cell adhesion molecule 6; epidermal growth factor receptor; n acetylglucosaminyltransferase; n acetylglucosaminyltransferase 5; protein antibody; tumor marker; unclassified drug; asparagine; CEACAM6 protein, human; cell adhesion molecule; EGFR protein, human; epidermal growth factor receptor; glycosylphosphatidylinositol anchored protein; leukocyte antigen; Mgat5 protein, human; n acetylglucosaminyltransferase; small interfering RNA; tumor marker; adult; animal experiment; animal model; animal tissue; Article; cancer recurrence; cancer staging; cancer tissue; cell invasion; cell migration; clinical article; controlled study; heavy chain; human; human cell; human tissue; intracellular signaling; male; metastasis; mouse; mouth squamous cell carcinoma; nonhuman; priority journal; protein domain; protein expression; protein function; protein glycosylation; protein localization; signal transduction; animal; cell motion; drug screening; genetics; glycosylation; lung tumor; metabolism; mouth tumor; pathology; SCID mouse; secondary; signal transduction; squamous cell carcinoma; tumor cell line; tumor invasion; tumor recurrence; Adult; Animals; Antigens, CD; Asparagine; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Glycosylation; GPI-Linked Proteins; Humans; Lung Neoplasms; Male; Mice; Mice, SCID; Mouth Neoplasms; N-Acetylglucosaminyltransferases; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Receptor, Epidermal Growth Factor; RNA, Small Interfering; Signal Transduction; Xenograft Model Antitumor Assays
Publisher
NATURE PUBLISHING GROUP
Type
journal article