O-glycan truncation enhances cancer-related functions of CD44 in gastric cancer

send to a friend share this

O-glycan truncation enhances cancer-related functions of CD44 in gastric cancer

Friday, 16.08.2019

CD44 isoforms are often upregulated in gastric cancer and have been associated with increased metastatic potential and poor survival. To evaluate the functional impact of O-glycan truncation on CD44 we have analysed glycoengineered cancer cell models displaying shortened O-glycans. Here, we demonstrate that induction of aberrant O-glycan termination through various molecular mechanisms affects CD44 molecular features. We show that CD44 is a major carrier of truncated O-glycans and that this truncation is accompanied by an increased hyaluronan binding capacity and affects extracellular shedding. In addition, short O-glycans promoted the colocalization of CD44v6 with the receptor tyrosine kinase RON and concomitantly increased activation. Our in vitro findings were validated in gastric cancer clinical samples.

 

Authors and Affiliations:

Mereiter S1,2, Martins ÁM1,2, Gomes C1,2, Balmaña M1,2, Macedo JA1,2, Polom K3,4, Roviello F4, Magalhães A1,2, Reis CA1,2,5,6.
  • 1 i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal.
  • 2 IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Portugal.
  • 3 Department of Surgical Oncology, Medical University of Gdansk, Poland.
  • 4 General Surgery and Surgical Oncology Department, University of Siena, Italy.
  • 5 Faculty of Medicine, University of Porto, Portugal.
  • 6 Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal.

 

Abstract:

CD44 isoforms are often upregulated in gastric cancer and have been associated with increased metastatic potential and poor survival. To evaluate the functional impact of O-glycan truncation on CD44 we have analysed glycoengineered cancer cell models displaying shortened O-glycans. Here, we demonstrate that induction of aberrant O-glycan termination through various molecular mechanisms affects CD44 molecular features. We show that CD44 is a major carrier of truncated O-glycans and that this truncation is accompanied by an increased hyaluronan binding capacity and affects extracellular shedding. In addition, short O-glycans promoted the colocalization of CD44v6 with the receptor tyrosine kinase RON and concomitantly increased activation. Our in vitro findings were validated in gastric cancer clinical samples.

 

Journal: FEBS Letters

 

Linkhttps://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1873-3468.13432