Abstract 1471: Glycoprotein 90K suppresses Wnt signaling via ISGylation-dependent ubiquitination of β-catenin that needs interaction with CD9/CD82

Backgrounds: Previously, we have observed that a tumor-associated 90K glycoprotein plays a potential tumor suppressor role in colorectal cancer (CRC) cells via antagonizing the canonical Wnt signaling pathway, which is functionally masked via interaction with extracellular galectin. Here, we investigated the signaling pathways of 90K action on CRC cells and its expression in human CRC tissues. Results: We identify a novel pathway 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 of ISG15 modification (ISGylation). 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 antitumor activity in CRC cells via suppression of Wnt signaling with a novel mechanism of ISGylation-dependent ubiquitination of β-catenin when it interacts with CD9/CD82, but is downregulated in advanced CRC tissues. Our data suggest a strategy of strengthening this novel pathway with concomitant knockdown of galectins as a potential therapeutic approach to CRC progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1471.