α1,4-Linked N-acetylglucosamine suppresses gastric cancer development by inhibiting Mucin-1-mediated signaling.
Cancer Sci
; 113(11): 3852-3863, 2022 Nov.
Article
en En
| MEDLINE
| ID: mdl-35959971
ABSTRACT
Gastric cancer is the second leading cause of cancer deaths worldwide, and more understanding of its molecular basis is urgently needed. Gastric gland mucin secreted from pyloric gland cells, mucous neck cells, and cardiac gland cells of the gastric mucosa harbors unique O-glycans carrying terminal α1,4-linked N-acetylglucosamine (αGlcNAc) residues. We previously reported that αGlcNAc loss correlated positively with poor outcomes for patients with differentiated-type gastric cancer. However, the molecular mechanisms underlying these outcomes remained poorly understood. Here, we examined the effects of upregulated αGlcNAc expression on malignant phenotypes of the differentiated-type gastric cancer cell lines, AGS and MKN7. Upregulation of αGlcNAc following ectopic expression of its biosynthetic enzyme attenuated cell proliferation, motility, and invasiveness of AGS and MKN7 cells in vitro. Moreover, AGS cell tumorigenicity was significantly suppressed by αGlcNAc overexpression in a xenograft model. To define the molecular mechanisms underlying these phenotypes, we investigated αGlcNAc binding proteins in AGS cells and identified Mucin-1 (MUC1) and podocalyxin. Both proteins were colocalized with αGlcNAc on human gastric cancer cells. We also found that αGlcNAc was bound to MUC1 in murine normal gastric mucosa. When we assessed the effects of αGlcNAc binding to MUC1, we found that αGlcNAc blocked galectin-3 binding to MUC1, phosphorylation of the MUC1 C-terminus, and recruitment of Src and ß-catenin to that C-terminus. These results suggest that αGlcNAc regulates cancer cell phenotypes by dampening MUC1 signal transduction.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Gástricas
/
Adenocarcinoma
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Sci
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón