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Glycoprotein 90K, downregulated in advanced colorectal cancer tissues, interacts with CD9/CD82 and suppresses the Wnt/ -catenin signal via ISGylation of -catenin
- Source :
- Gut. 59:907-917
- Publication Year :
- 2010
- Publisher :
- BMJ, 2010.
-
Abstract
- Background and aims 90K, a tumour-associated glycoprotein, interacts with galectins and has roles in host defence by augmenting the immune response, but the serum 90K level was suggested to indicate poor prognosis in several cancers. The cellular mechanisms of 90K action on colorectal cancer (CRC) cell motility and its effect on CRC progression were investigated. Methods The impact of 90K was analysed by combining cell cultures, in vitro assays, and immunohistochemistry. Results Secreted 90K suppresses CRC cell invasion, but this action of 90K is masked through binding with extracellular galectins. A novel pathway is identified comprising a secretory 90K and a CD9/CD82 tetraspanin web; in this pathway, 90K interacts with CD9/CD82, suppresses the Wnt/β-catenin signal via a novel proteasomal-ubiquitination mechanism of β-catenin that is dependent on ISG15 (interferon-stimulated gene-15) modification (ISGylation) but not on glycogen synthase kinase 3β (GSK-3β) and Siah/Adenomatous polyposis coli (APC). In a syngeneic mouse colon tumour model, tumour growth and lung metastasis were increased with 90K knockdown. In colon tissues from stage IV human CRC and invading cancer cells of corresponding metastatic liver tissues, in which β-catenin and galectin expression was higher, immunostained 90K and CD9/CD82 were lower than in adjacent hepatic tissues or colon tissues from stage I. Conclusions 90K itself has antitumour activity in CRC cells via suppression of Wnt signalling with a novel mechanism of ISGylation-dependent ubiquitination of β-catenin when it interacts with CD9/CD82, but is downregulated in advanced CRC tissues. The data suggest a strategy of strengthening this novel pathway with concomitant knockdown of galectins as a potential therapeutic approach to CRC progression.
- Subjects :
- medicine.medical_specialty
Lung Neoplasms
Colorectal cancer
Adenomatous polyposis coli
Galectins
Down-Regulation
Lactose
Biology
Kangai-1 Protein
Tetraspanin 29
Mice
Antigens, CD
Antigens, Neoplasm
Cell Movement
GSK-3
Internal medicine
Biomarkers, Tumor
Tumor Cells, Cultured
medicine
Animals
Humans
Ubiquitins
beta Catenin
Cell Proliferation
Glycoproteins
Galectin
Membrane Glycoproteins
Ubiquitin
Liver Neoplasms
Gastroenterology
Wnt signaling pathway
medicine.disease
ISG15
Neoplasm Proteins
Wnt Proteins
Disease Models, Animal
Endocrinology
Culture Media, Conditioned
Catenin
Cancer cell
Cancer research
biology.protein
Cytokines
Carrier Proteins
Colorectal Neoplasms
Signal Transduction
Subjects
Details
- ISSN :
- 00175749
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Gut
- Accession number :
- edsair.doi.dedup.....432182b3fb8cc7ec7af51db2a1248388