Abstract
Glycoprotein 90K (also known as LGALS3BP or Mac-2BP) is a tumor-associated protein, and high 90K levels are associated with poor prognosis in some cancers. To clarify the role of 90K as an indicator for poor prognosis and metastasis in epithelial cancers, the present study investigated the effect of 90K on an adherens junctional protein, E-cadherin, which is frequently absent or downregulated in human epithelial cancers. Treatment of certain cancer cells with 90K significantly reduced E-cadherin levels in a cell-population-dependent manner, and these cells showed decreases in cell adhesion and increases in invasive cell motility. Mechanistically, 90K-induced E-cadherin downregulation occurred via ubiquitination-mediated proteasomal degradation. 90K interacted with the E-cadherin–p120-catenin complex and induced its dissociation, altering the phosphorylation status of p120-catenin, whereas it did not associate with β-catenin. In subconfluent cells, 90K decreased membrane-localized p120-catenin and the membrane fraction of the p120-catenin. Particularly, 90K-induced E-cadherin downregulation was diminished in p120-catenin knocked-down cells. Taken together, 90K upregulation promotes the dissociation of the E-cadherin–p120-catenin complex, leading to E-cadherin proteasomal degradation, and thereby destabilizing adherens junctions in less confluent tumor cells. Our results provide a potential mechanism to explain the poor prognosis of cancer patients with high serum 90K levels.
Highlights
The protein known as lectin galactoside-binding soluble 3-binding protein (LGALS3BP), Mac-2-binding protein (Mac-2BP), or 90K is a secretory glycoprotein, and its serum levels are observed to be elevated in several cancers and viral infections
As 90K plays a role in immune defense and immune regulation, its levels are increased in patients with human immunodeficiency virus [1], hepatitis C virus [2], hantavirus [3], or dengue virus [4] infection. 90K was originally identified as a tumor-associated antigen that is released in the culture media of human breast cancer cells [5], and it has both negative and positive effects on the prognosis of various cancers [6]
As the upregulation of 90K in several cancers including colon, prostate, lung, and breast suggests an association between 90K and tumorigenesis [7,9,11,12], and E-cadherin depletion is directly related to migratory and metastatic properties of the cancer cell, here we aimed to analyze the effects of 90K on E-cadherin levels in cancer cell types that are known to exhibit varying degrees of migratory capability
Summary
The protein known as lectin galactoside-binding soluble 3-binding protein (LGALS3BP), Mac-2-binding protein (Mac-2BP), or 90K is a secretory glycoprotein, and its serum levels are observed to be elevated in several cancers and viral infections. A high (>11 μg/mL) serum level of 90K in breast cancer patients was reported as a poor prognostic factor [16] and associated with distant recurrence [12], and enriched 90K was found from secreted exosomes of ovarian carcinoma cells [17]. Increased expression of 90K by immunohistochemistry is correlated with poor disease-free and overall survival in patients with non-small-cell lung cancer [11]. 90K is downregulated in advanced colorectal cancer (CRC) tissues and invading cancer cells of corresponding metastatic liver tissues [19]. Taken together, these findings indicate that the role of 90K in cancer is dependent on the specific microenvironment of differentiated cancer cells
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