Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level

Kristin E. Haugstad, Thomas A. Gerken, Bjørn T. Stokke, Tarun K. Dam, Curtis F. Brewer, Marit Sletmoen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Mucins are linear O-glycosylated glycoproteins involved in inflammation, cell adhesion, and tumorigenesis. Cancer-associated mucins often possess increased expression of the T (Galβ1,3GalNAcαThr/Ser) and Tn (GalNAcαThr/Ser) cancer antigens, which are diagnostic markers for several cancers, including colon cancer. We have used AFM based single-molecule forced unbinding under near physiological conditions to investigate the self-interactions between porcine submaxillary mucin (PSM) as well as between PSM analogs possessing various carbohydrates including the T- and Tn-antigen. Distributions of unbinding forces and corresponding force loading rates were determined for force loading rates from 0.18 nN/s to 39 nN/s, and processed to yield most probable unbinding forces f* and lifetimes of the interactions. Parameter f* varied in the range 27 to 50 pN at force loading rates of about 2 nN/s among the various mucins. All mucin samples investigated showed self-interaction, but the tendency was greatest for PSM displaying only the Tn-antigen (Tn-PSM) or a mixture of Tn-, T-antigen, and the trisaccharide Fucα1,2Galβ1,3GalNAc (Tri-PSM). Weaker self-interactions were observed for native PSM (Fd-PSM), which consists of a nearly equal mixture of the longer core 1 blood group A tetrasaccharide (GalNAcα1,3(Fucα1,2) Galβ1,3GalNAcαSer/Thr) and Tn-antigen. The data are consistent with the truncated Tn and T glycans enhancing self-interaction of the mucins. These carbohydrate cancer antigens may, thus, play an active role in the disease by constitutively activating mucin and mucin-type receptors by self-association on cells.

Original languageEnglish (US)
Pages (from-to)1400-1409
Number of pages10
JournalBiomacromolecules
Volume13
Issue number5
DOIs
StatePublished - May 14 2012

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Mucins
Antigens
Carbohydrates
Molecules
Glycoproteins
Cell adhesion
Viral Tumor Antigens
Blood
Trisaccharides
Blood Group Antigens
Polysaccharides

ASJC Scopus subject areas

  • Bioengineering
  • Materials Chemistry
  • Polymers and Plastics
  • Biomaterials

Cite this

Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level. / Haugstad, Kristin E.; Gerken, Thomas A.; Stokke, Bjørn T.; Dam, Tarun K.; Brewer, Curtis F.; Sletmoen, Marit.

In: Biomacromolecules, Vol. 13, No. 5, 14.05.2012, p. 1400-1409.

Research output: Contribution to journalArticle

Haugstad, Kristin E. ; Gerken, Thomas A. ; Stokke, Bjørn T. ; Dam, Tarun K. ; Brewer, Curtis F. ; Sletmoen, Marit. / Enhanced self-association of mucins possessing the T and Tn carbohydrate cancer antigens at the single-molecule level. In: Biomacromolecules. 2012 ; Vol. 13, No. 5. pp. 1400-1409.
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abstract = "Mucins are linear O-glycosylated glycoproteins involved in inflammation, cell adhesion, and tumorigenesis. Cancer-associated mucins often possess increased expression of the T (Galβ1,3GalNAcαThr/Ser) and Tn (GalNAcαThr/Ser) cancer antigens, which are diagnostic markers for several cancers, including colon cancer. We have used AFM based single-molecule forced unbinding under near physiological conditions to investigate the self-interactions between porcine submaxillary mucin (PSM) as well as between PSM analogs possessing various carbohydrates including the T- and Tn-antigen. Distributions of unbinding forces and corresponding force loading rates were determined for force loading rates from 0.18 nN/s to 39 nN/s, and processed to yield most probable unbinding forces f* and lifetimes of the interactions. Parameter f* varied in the range 27 to 50 pN at force loading rates of about 2 nN/s among the various mucins. All mucin samples investigated showed self-interaction, but the tendency was greatest for PSM displaying only the Tn-antigen (Tn-PSM) or a mixture of Tn-, T-antigen, and the trisaccharide Fucα1,2Galβ1,3GalNAc (Tri-PSM). Weaker self-interactions were observed for native PSM (Fd-PSM), which consists of a nearly equal mixture of the longer core 1 blood group A tetrasaccharide (GalNAcα1,3(Fucα1,2) Galβ1,3GalNAcαSer/Thr) and Tn-antigen. The data are consistent with the truncated Tn and T glycans enhancing self-interaction of the mucins. These carbohydrate cancer antigens may, thus, play an active role in the disease by constitutively activating mucin and mucin-type receptors by self-association on cells.",
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