2. Academic Validation
  3. 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

  • Oncogene. 2018 Jan 4;37(1):116-127. doi: 10.1038/onc.2017.303.
W-F Chiang 1 2 3,  T-M Cheng 1,  C-C Chang 1 4,  S-H Pan 5 6 7,  C A Changou 1 8,  T-H Chang 9,  K-H Lee 8,  S-Y Wu 10 11,  Y-F Chen 12,  K-H Chuang 13,  D-B Shieh 14 15,  Y-L Chen 14,  C-C Tu 16,  W-L Tsui 1,  M-H Wu 1 9 17
Affiliations

Affiliations

  • 1 Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
  • 2 Oral and Maxillofacial Section, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
  • 3 School of Dentistry, National Yang Ming University, Taipei, Taiwan.
  • 4 Ph.D Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 5 Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 6 Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.
  • 7 Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, Taiwan.
  • 8 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
  • 9 Graduate Institute of Biomedical Informatics, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan.
  • 10 Department of Radiation Oncology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 11 Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 12 Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City, Taiwan.
  • 13 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 14 Institute of Basic Medical Science, Institute of Oral Medicine and Department of Stomatology, College of Medicine, National Cheng Kung University and hospital, Tainan, Taiwan.
  • 15 Advanced Optoelectronic Technology Center and Center for Micro/Nano Science and Technology, National Cheng Kung University, Tainan, Taiwan.
  • 16 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 17 Center for Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei, Taiwan.
PMID: 28892050 DOI: 10.1038/onc.2017.303
Abstract

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 Asn256 (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.

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