Article Text

PDF
Glycoprotein 90K, downregulated in advanced colorectal cancer tissues, interacts with CD9/CD82 and suppresses the Wnt/β-catenin signal via ISGylation of β-catenin
  1. Ji Hee Lee1,
  2. Jeong A Bae1,
  3. Jae Hyuk Lee3,
  4. Young-Woo Seo4,
  5. Dhong Hyo Kho1,
  6. Eun Gene Sun1,
  7. Song Eun Lee1,
  8. Sang Hee Cho2,
  9. Young Eun Joo5,
  10. Kyu Youn Ahn1,
  11. Ik Joo Chung2,
  12. Kyung Keun Kim1
  1. 1Medical Research Center for Gene Regulation and the Brain Korea 21 Project, Kwangju, Korea
  2. 2Department of Hematology-Oncology, Chonnam National University Medical School, Kwangju, Korea
  3. 3Department of Pathology, Chonnam National University Medical School, Kwangju, Korea
  4. 4Korea Basic Science Institute, Kwangju Center, Kwangju, Korea
  5. 5Department of Gastroenterology-Hepatology, Chonnam National University Medical School, Kwangju, Korea
  1. Correspondence to Dr Kyung Keun Kim, Department of Pharmacology, Chonnam National University Medical School, Hak-Dong 5, Dong-Ku, Kwangju 501-190, Korea; kimkk{at}chonnam.ac.kr

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.

Statistics from Altmetric.com

Footnotes

  • JHL and JAB contributed equally to this work.

  • Funding Korea Science & Engineering Foundation.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Ethics Committee of Chonnam National University Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.